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Ren C, Chen M, Ren B, Zeng Y, Tan Q, Li Q, Zhang X, Fang Y, Zhou Y, Zhang W, Chen F, Bian B, Liu Y. Mesenchymal stem cell-derived small extracellular vesicles enhance the therapeutic effect of retinal progenitor cells in retinal degenerative disease rats. Neural Regen Res 2026; 21:821-832. [PMID: 39101643 DOI: 10.4103/nrr.nrr-d-23-02108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 06/08/2024] [Indexed: 08/06/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202602000-00050/figure1/v/2025-05-05T160104Z/r/image-tiff Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone. Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles. Small extracellular vesicles derived from bone marrow mesenchymal stem cells, which offer low immunogenicity, minimal tumorigenic risk, and ease of transportation, have been utilized in the treatment of various neurological diseases. These vesicles exhibit various activities, including anti-inflammatory actions, promotion of tissue repair, and immune regulation. Therefore, novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration. In this study, we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats, a genetic model of retinal degeneration. Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats. The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival, migration, and differentiation of the exogenous retinal progenitor cells. Concurrently, these small extracellular vesicles inhibited the activation of regional microglia, promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina, and facilitated their differentiation into photoreceptors and bipolar cells. These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.
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Affiliation(s)
- Chunge Ren
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Min Chen
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Bangqi Ren
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Yuxiao Zeng
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Qiang Tan
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Qiyou Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Xue Zhang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Yajie Fang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Yixiao Zhou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Weitao Zhang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Fang Chen
- Department of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Baishijiao Bian
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
- Army 953 Hospital, Shigatse Branch of Xinqiao Hospital, Third Military Medical University (Army Medical University), Shigatse, Tibet Autonomous Region, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yong Liu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
- Jinfeng Laboratory, Chongqing, China
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Chen H, Li N, Cai Y, Ma C, Ye Y, Shi X, Guo J, Han Z, Liu Y, Wei X. Exosomes in neurodegenerative diseases: Therapeutic potential and modification methods. Neural Regen Res 2026; 21:478-490. [PMID: 40326981 DOI: 10.4103/nrr.nrr-d-24-00720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 10/14/2024] [Indexed: 05/07/2025] Open
Abstract
In recent years, exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research. Exosomes are small and can effectively cross the blood-brain barrier, allowing them to target deep brain lesions. Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines, mRNAs, and disease-related proteins, thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects. However, exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells. This limitation can lead to side effects and toxicity when they interact with non-specific cells. Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases. In this review, we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases. Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases. We introduce the strategies being used to enhance exosome targeting, including genetic engineering, chemical modifications (both covalent, such as click chemistry and metabolic engineering, and non-covalent, such as polyvalent electrostatic and hydrophobic interactions, ligand-receptor binding, aptamer-based modifications, and the incorporation of CP05-anchored peptides), and nanomaterial modifications. Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases. However, several challenges remain in the clinical application of exosomes. Improvements are needed in preparation, characterization, and optimization methods, as well as in reducing the adverse reactions associated with their use. Additionally, the range of applications and the safety of exosomes require further research and evaluation.
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Affiliation(s)
- Hongli Chen
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
| | - Na Li
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
| | - Yuanhao Cai
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
- School of Intelligent Information Engineering, Medicine & Technology College of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Chunyan Ma
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
| | - Yutong Ye
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
| | - Xinyu Shi
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
| | - Jun Guo
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
| | - Zhibo Han
- Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceuticals, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China
| | - Yi Liu
- State Key Laboratory of Separation Membrane and Membrane Process & Tianjin Key Laboratory of Optoelectronic Detection Technology and Systems, School of Life Sciences, Tiangong University, Tianjin, China
| | - Xunbin Wei
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Cancer Hospital & Institute, International Cancer Institute, Institute of Medical Technology, Peking University Health Science Center, Department of Biomedical Engineering, Peking University, Beijing, China
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Chen Y, Cui F, Wu X, Zhao W, Xia Q. The expression and clinical significance of serum exosomal-long non-coding RNA DLEU1 in patients with cervical cancer. Ann Med 2025; 57:2442537. [PMID: 39687982 DOI: 10.1080/07853890.2024.2442537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/25/2024] [Accepted: 11/23/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Accumulating evidence has demonstrated that the long non-coding RNA (lncRNA) lymphocytic leukaemia deletion gene 1 (DLEU1) is abnormally overexpressed in many cancer types, including cervical cancer (CC). However, the potential clinical significance of DLEU1 in serum exosomes of patients with CC remains unclear. METHODS The expression of serum exosomal DLEU1 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). A receiver operating characteristic (ROC) curve was plotted to evaluate the clinical diagnostic efficacy of DLEU1. The Kaplan-Meier survival curve and Cox proportional hazards model were used to assess the effect of DLEU1 on postoperative recurrence, metastasis and prognosis among patients with CC. RESULTS Our research showed that DLEU1 expression in the serum exosomes of patients with CC was significantly upregulated compared to that in patients with cervical intraepithelial neoplasia (CIN) and healthy controls (HCs) (both p < .001). DLEU1 relative expression was significantly correlated with tumour size, cervical invasion depth, pathological grade, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis among patients with CC (p < .01 all). The combined detection of DLEU1, carbohydrate antigen 125 (CA-125) and squamous cell carcinoma (SCC) exhibited significantly higher diagnostic efficiency (p < .01). Furthermore, the overall survival (OS) and disease-free survival (DFS) of CC patients in the high DLEU1 expression group were markedly lower than those in the low DLEU1 expression group (both p < .01). Cox univariate and multivariate regression analyses indicated that DLEU1 was an independent risk factor for postoperative recurrence and metastasis in CC patients. CONCLUSIONS Our findings suggest that serum exosome DLEU1 has certain clinical value for diagnosing, monitoring recurrence and metastasis, and evaluating CC prognosis.
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Affiliation(s)
- Yu Chen
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, PR China
| | - Facai Cui
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Xiaoyu Wu
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Weifeng Zhao
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, PR China
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Batur A, Novak R, Salai G, Hrkač S, Ćosić V, Grgurević L. Extracellular vesicles in the pathogenesis and future diagnostics of oral squamous cell carcinoma. Future Sci OA 2025; 11:2461940. [PMID: 39920887 PMCID: PMC11812389 DOI: 10.1080/20565623.2025.2461940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/13/2025] [Indexed: 02/09/2025] Open
Abstract
Extracellular vesicles are a group of heterogeneous particles secreted during both physiological and pathological conditions which serve in intercellular communication and play a role in the development and progression of oral squamous cell carcinoma, the most common malignant tumor of the head and neck with a high mortality rate. Extensive research is being conducted in order to determine the precise role of extracellular vesicles in oncogenic processes and to explore the possible application of extracellular vesicles as early tumor biomarkers. In this review, we aimed to systematize observed roles extracellular vesicles might play in organizing of tumor microenvironment, tumor invasion and metastasis, as well as the impact of extracellular vesicles on immune dysregulation and development of resistance to chemotherapeutics. Additionally, we summarized findings involving the potential use of extracellular vesicles cargo proteins as early disease biomarkers.
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Affiliation(s)
- Anđela Batur
- School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Ruđer Novak
- Center for Translational and Clinical Research, Department of Proteomics, University of Zagreb, School of Medicine, Zagreb, Croatia
- BIMIS – Biomedical Research Center Šalata, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Grgur Salai
- Department of Pulmonology, University Hospital Dubrava, Zagreb, Croatia
| | - Stela Hrkač
- Department of Clinical Immunology, Allergology and Rheumatology, University Hospital Dubrava, Zagreb, Croatia
| | - Vesna Ćosić
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Lovorka Grgurević
- Center for Translational and Clinical Research, Department of Proteomics, University of Zagreb, School of Medicine, Zagreb, Croatia
- BIMIS – Biomedical Research Center Šalata, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Anatomy, “Drago Perović”, University of Zagreb, School of Medicine, Zagreb, Croatia
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Lv Y, Li Y, Zhou J, Liu X, Wang D, Wang D, Tong D, Wang S, An H, Kang X. Exosomal miR-122-5p for regulation of secretory functions of fibroblasts and promotion of breast cancer metastasis by targeting MKP-2: an experimental study. Cancer Biol Ther 2025; 26:2500104. [PMID: 40320567 PMCID: PMC12051585 DOI: 10.1080/15384047.2025.2500104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 12/14/2024] [Accepted: 04/27/2025] [Indexed: 05/08/2025] Open
Abstract
Tumor metastasis is a major obstacle for the effective treatment of breast cancer. Some studies showed that exosomes could promote tumor distant metastasis by establishing pre-metastasis niches (PMN). MicroRNAs (miRNAs) in exosomes play a critical role in tumor development and invasion. We aimed to investigate the effects of exosomal miRNAs derived from breast cancer cells on metastasis. MiRNA sequencing and RT-PCR approach were used to screen potential exosomal miRNAs. We compared the levels of serum exosomal miRNAs from breast cancer patients and those from MCF10A/MCF7/MDA-MB-231 cells. We found that differential exosomal miRNAs screened from patients with metastasis have higher expression levels in exosomes secreted by MDA-MB-231 cells. Using miRNA mimics or inhibitors, exosomal miR-122-5p was found to enhance the secretion levels of chemokine MCP-1 and SDF-1 from WI-38 lung fibroblast cells. In vitro luciferase assay and western blot confirmed the targeting of 3'-untranslated region of MKP-2 and suppression of MKP-2 expression by miR-122-5p in WI-38 cells. Treatment of xenograft mice with exosomal miR-122-5p increased the levels of MCP-1 and SDF-1 in serum, and promoted lung metastasis of breast cancer. In conclusion, we identified exosomal miR-122-5p from breast cancer cells that could promote the chemokine secretion of lung fibroblasts, which might facilitate the chemotaxis and colonization of breast cancer cells in lung tissue.
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Affiliation(s)
- Yun Lv
- Department of Medical Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yue Li
- Department of Medical Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Jie Zhou
- Department of Medical Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xin Liu
- Department of Medical Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Dandan Wang
- Department of Medical Oncology, Heze Municipal Hospital, Heze, China
| | - Dongmei Wang
- Department of Ultrasonography, Xiang’an Hospital of Xiamen University, Xiamen, China
| | - Dandan Tong
- School of medicine, Huaqiao University, Quanzhou, China
| | - Shuhuai Wang
- Department of Pathology, Cancer Hospital of Harbin Medical University, Harbin, China
| | - Hanxiang An
- Department of Medical Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xinmei Kang
- Department of Medical Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Key Laboratory of Endocrine-Related Cancer Precision Medicine, School of Medicine, Xiamen University, Xiamen, China
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6
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Chi J, Fan B, Li Y, Jiao Q, Li GY. Mitochondrial transplantation: a promising strategy for the treatment of retinal degenerative diseases. Neural Regen Res 2025; 20:3370-3387. [PMID: 39851134 PMCID: PMC11974652 DOI: 10.4103/nrr.nrr-d-24-00851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/11/2024] [Accepted: 10/24/2024] [Indexed: 01/26/2025] Open
Abstract
The retina, a crucial neural tissue, is responsible for transforming light signals into visual information, a process that necessitates a significant amount of energy. Mitochondria, the primary powerhouses of the cell, play an integral role in retinal physiology by fulfilling the high-energy requirements of photoreceptors and secondary neurons through oxidative phosphorylation. In a healthy state, mitochondria ensure proper visual function by facilitating efficient conversion and transduction of visual signals. However, in retinal degenerative diseases, mitochondrial dysfunction significantly contributes to disease progression, involving a decline in membrane potential, the occurrence of DNA mutations, increased oxidative stress, and imbalances in quality-control mechanisms. These abnormalities lead to an inadequate energy supply, the exacerbation of oxidative damage, and the activation of cell death pathways, ultimately resulting in neuronal injury and dysfunction in the retina. Mitochondrial transplantation has emerged as a promising strategy for addressing these challenges. This procedure aims to restore metabolic activity and function in compromised cells through the introduction of healthy mitochondria, thereby enhancing the cellular energy production capacity and offering new strategies for the treatment of retinal degenerative diseases. Although mitochondrial transplantation presents operational and safety challenges that require further investigation, it has demonstrated potential for reviving the vitality of retinal neurons. This review offers a comprehensive examination of the principles and techniques underlying mitochondrial transplantation and its prospects for application in retinal degenerative diseases, while also delving into the associated technical and safety challenges, thereby providing references and insights for future research and treatment.
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Affiliation(s)
- Jing Chi
- Department of Ophthalmology, The Second Norman Bethune Hospital of Jilin University, Changchun, Jilin Province, China
| | - Bin Fan
- Department of Ophthalmology, The Second Norman Bethune Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yulin Li
- Department of Ophthalmology, The Second Norman Bethune Hospital of Jilin University, Changchun, Jilin Province, China
| | - Qing Jiao
- Department of Ophthalmology, The Second Norman Bethune Hospital of Jilin University, Changchun, Jilin Province, China
| | - Guang-Yu Li
- Department of Ophthalmology, The Second Norman Bethune Hospital of Jilin University, Changchun, Jilin Province, China
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Yang X, Gao X, Jiang X, Yue K, Luo P. Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases. Neural Regen Res 2025; 20:3076-3094. [PMID: 39435635 PMCID: PMC11881733 DOI: 10.4103/nrr.nrr-d-24-00462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/15/2024] [Accepted: 09/07/2024] [Indexed: 10/23/2024] Open
Abstract
Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.
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Affiliation(s)
- Xinyu Yang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Xiangyu Gao
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Xiaofan Jiang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Kangyi Yue
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Peng Luo
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
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Aldali F, Deng C, Nie M, Chen H. Advances in therapies using mesenchymal stem cells and their exosomes for treatment of peripheral nerve injury: state of the art and future perspectives. Neural Regen Res 2025; 20:3151-3171. [PMID: 39435603 PMCID: PMC11881730 DOI: 10.4103/nrr.nrr-d-24-00235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/26/2024] [Accepted: 08/26/2024] [Indexed: 10/23/2024] Open
Abstract
"Peripheral nerve injury" refers to damage or trauma affecting nerves outside the brain and spinal cord. Peripheral nerve injury results in movements or sensation impairments, and represents a serious public health problem. Although severed peripheral nerves have been effectively joined and various therapies have been offered, recovery of sensory or motor functions remains limited, and efficacious therapies for complete repair of a nerve injury remain elusive. The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function. Mesenchymal stem cells, as large living cells responsive to the environment, secrete various factors and exosomes. The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins, microRNA, and messenger RNA derived from parent mesenchymal stem cells. Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function, offering solutions to changes associated with cell-based therapies. Despite ongoing investigations, mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage. A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation. This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury, exploring the underlying mechanisms. Subsequently, it provides an overview of the current status of mesenchymal stem cell and exosome-based therapies in clinical trials, followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes. Finally, the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes, offering potential solutions and guiding future directions.
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Affiliation(s)
- Fatima Aldali
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Chunchu Deng
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mingbo Nie
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hong Chen
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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9
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Jia M, Wang C, Chen M, Dong W, Zhang H, Ou J, Wei Y. TiO 2-coated honeycomb-like super-macroporous silica for high-purity extraction of exosomes from human plasma. Talanta 2025; 293:128098. [PMID: 40215722 DOI: 10.1016/j.talanta.2025.128098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 03/20/2025] [Accepted: 04/05/2025] [Indexed: 05/14/2025]
Abstract
Screening biomarkers from exosomes has emerged as a new strategy for non-invasive early diagnosis of diseases. Nevertheless, the present screening efficiency and accuracy of biomarkers are limited by the low extraction efficiency and purity of exosomes. To address this issue, a highly selective adsorbent, which integrates size-exclusion and chemisorption, was created by coating TiO2 on honeycomb-like super-macroporous silica. Cell culture medium and human plasma were employed to investigate the enrichment performance, and the results indicate that the super-macropores ranging from 63.5 to 147.5 nm together with thin pore walls allow exosomes to enter and be adsorbed by TiO2 in the pores, enhancing the available surface area for exosomes meanwhile physically excluding the large-sized cell debris and vesicles. Taking advantages of these properties, the prepared adsorbent achieves a higher extraction efficiency, recovery and purity of exosomes compared with the normal adsorbents and ultracentrifugation (UC) method. Combining this method with proteomic analysis, a total of 392 proteins were identified in exosomes from healthy human plasma, which is significantly higher than the number obtained by UC (200 proteins). For clinical samples, 59 upregulated and 124 downregulated proteins were identified in the plasma from colorectal cancer (CRC) patients, of which 44 upregulated proteins and 69 downregulated proteins are strongly associated with the progression of CRC. These findings suggest that this adsorbent possesses considerable potential in the extraction of exosomes for screening biomarkers and diagnosing tumor progress.
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Affiliation(s)
- Mengqian Jia
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, 710127, China
| | - Chenyang Wang
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, 710127, China
| | - Mengxi Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Wenzhuo Dong
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, 710127, China
| | - Haiyang Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
| | - Junjie Ou
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, 710127, China
| | - Yinmao Wei
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, 710127, China.
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Woo HK, Nam Y, Park HG, Lee H. Bridging laboratory innovation to translational research and commercialization of extracellular vesicle isolation and detection. Biosens Bioelectron 2025; 282:117475. [PMID: 40300344 PMCID: PMC12076185 DOI: 10.1016/j.bios.2025.117475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 03/04/2025] [Accepted: 04/13/2025] [Indexed: 05/01/2025]
Abstract
Extracellular vesicles (EVs) have emerged as promising biomarkers for various diseases. Encapsulating biomolecules reflective of their parental cells, EVs are readily accessible in bodily fluids. The prospect for minimally invasive, repeatable molecular testing has stimulated significant research; however, challenges persist in isolating EVs from complex biological matrices and characterizing their limited molecular cargo. Technical advances have been pursued to address these challenges, producing innovative EV-specific platforms. This review highlights recent technological developments, focusing on EV isolation and molecular detection methodologies. Furthermore, it explores the translation of these laboratory innovations to clinical applications through the analysis of patient samples, providing insights into the potential diagnostic and prognostic utility of EV-based technologies.
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Affiliation(s)
- Hyun-Kyung Woo
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yoonho Nam
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Chemical and Biomolecular Engineering (BK21 Four), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Hyun Gyu Park
- Department of Chemical and Biomolecular Engineering (BK21 Four), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
| | - Hakho Lee
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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11
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Wang Z, Sun Z, Zhu S, Qin Z, Yin X, Ding Y, Gao H, Cao X. A multifunctional hydrogel loaded with magnesium-doped bioactive glass-induced vesicle clusters enhances diabetic wound healing by promoting intracellular delivery of extracellular vesicles. Bioact Mater 2025; 50:30-46. [PMID: 40242508 PMCID: PMC11998110 DOI: 10.1016/j.bioactmat.2025.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 03/04/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
The treatment of diabetic wounds (DWs) poses a significant medical challenge. Mesenchymal stem cell-derived small extracellular vesicles (sEVs) have demonstrated potential in accelerating healing by delivering growth factors and microRNAs. However, the rapid clearance by the circulatory system limits their concentration and bioavailability within cells. This study employed magnesium-doped bioactive glass (MgBG) to autonomously program sEVs into a vesicle cluster (EPPM), which was subsequently incorporated into a hydrogel to create a comprehensive repair system that enhanced the delivery of both sEVs and MgBG, thereby promoting rapid healing of diabetic wounds. This hydrogel exhibited excellent injectable, self-healing and bioadhesive properties, making it an ideal physical barrier for DWs. In addition, the hydrogels also possessed photoresponsive properties that facilitated their bactericidal activity. The released EPPM significantly increased the intracellular uptake and accumulation of sEVs, with approximately 8.2-fold enhancement in macrophages and 16.7-fold in endothelial cells. The EPPM clusters efficiently induce macrophage M2 polarization, reduce inflammatory responses at the wound site, and recruit cells, thereby promoting angiogenesis and collagen deposition. This integrated repair system provided a new platform for the comprehensive treatment of diabetic wounds.
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Affiliation(s)
- Zetao Wang
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China
- National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou, 510006, PR China
- Centre for Translational Medicine Research & Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
| | - Zhipeng Sun
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China
- National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou, 510006, PR China
| | - Shuangli Zhu
- Institute of Medical Health, Harbin Institute of Technology Zhengzhou Research Institute, Zhengzhou, 450000, PR China
| | - Zhihao Qin
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China
- National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou, 510006, PR China
| | - Xiaohong Yin
- Institute of Medical Health, Harbin Institute of Technology Zhengzhou Research Institute, Zhengzhou, 450000, PR China
| | - Yilin Ding
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China
- National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou, 510006, PR China
| | - Huichang Gao
- School of Medicine, South China University of Technology, Guangzhou, 510006, PR China
| | - Xiaodong Cao
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, PR China
- National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou, 510006, PR China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, 510006, PR China
- Zhongshan Institute of Modern Industrial Technology of SCUT, Zhongshan, Guangdong, 528437, PR China
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12
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Yang S, Zhu H, Jin H, Wang K, Song J, Sun N, Liu Y, Yin X, Wang R, Wu X, Liu H, Zhang C, Zhao W, Yu F. Bio-orthogonal-labeled exosomes reveals specific distribution in vivo and provides potential application in ARDS therapy. Biomaterials 2025; 319:123208. [PMID: 40023928 DOI: 10.1016/j.biomaterials.2025.123208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/15/2025] [Accepted: 02/23/2025] [Indexed: 03/04/2025]
Abstract
Exosomes derived from specific cells may be useful for targeted drug delivery, but tracking them in vivo is essential for their clinical application. However, their small size and complex structure challenge the development of exosome-tracking techniques, and traditional labeling methods are limited by weak affinity and potential toxicity. To address these issues, here we developed a novel bio-orthogonal labeling strategy based on phosphatidylinositol derivatives to fluorescently label exosomes from various human and mouse cell types. The different cell-derived exosomes revealed organ-specific distribution patterns and a favorable safety profile. Notably, 4T1 cell-derived exosomes specifically targeted the lungs. When used as drug carriers loaded with anti-inflammatory resveratrol, these exosomes showed significant therapeutic efficacy in mice with acute respiratory distress syndrome (ARDS), effectively reducing inflammatory responses, mitigating pulmonary fibrosis, and restoring lung tissue morphology and function. Our findings provide a novel exosome labeling strategy and an invaluable tool for their in vivo tracking and targeting screening, while exosomes that specifically target the lungs offer a potential therapeutic strategy for organ-specific diseases such as ARDS.
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Affiliation(s)
- Song Yang
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Haomiao Zhu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China; Department of Pharmacy, Qilu Hospital, Shandong University, No.107 Cultural West Road, Jinan, 250012, China
| | - Hongzhen Jin
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Kun Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Junna Song
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Na Sun
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China
| | - Yonghui Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China; School of Chemistry, Tiangong University, No.399 BinShuiXi Road, Tianjin, 300387, China
| | - Xiaona Yin
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Rui Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Xiao Wu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China
| | - Huadong Liu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China
| | - Chunling Zhang
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China.
| | - Wei Zhao
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China.
| | - Fan Yu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China.
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13
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Chen J, Li Y, Quan X, Chen J, Han Y, Yang L, Zhou M, Mok GSP, Wang R, Zhao Y. Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke: a special outlook on mitochondrial delivery. Neural Regen Res 2025; 20:2181-2198. [PMID: 39101653 PMCID: PMC11759020 DOI: 10.4103/nrr.nrr-d-24-00243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/03/2024] [Accepted: 06/22/2024] [Indexed: 08/06/2024] Open
Abstract
Ischemic stroke is a secondary cause of mortality worldwide, imposing considerable medical and economic burdens on society. Extracellular vesicles, serving as natural nano-carriers for drug delivery, exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke. However, the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency. By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles, their delivery efficacy may be greatly improved. Furthermore, previous studies have indicated that microvesicles, a subset of large-sized extracellular vesicles, can transport mitochondria to neighboring cells, thereby aiding in the restoration of mitochondrial function post-ischemic stroke. Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components, such as proteins or deoxyribonucleic acid, or their sub-components, for extracellular vesicle-based ischemic stroke therapy. In this review, we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies. Given the complex facets of treating ischemic stroke, we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process. Moreover, given the burgeoning interest in mitochondrial delivery, we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.
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Affiliation(s)
- Jiali Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Yiyang Li
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Xingping Quan
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Jinfen Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Yan Han
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Li Yang
- Department of Pharmacy, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
| | - Manfei Zhou
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Greta Seng Peng Mok
- Department of Electrical and Computer Engineering, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Ruibing Wang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Yonghua Zhao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region, China
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14
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Yu L, Shi H, Gao T, Xu W, Qian H, Jiang J, Yang X, Zhang X. Exomeres and supermeres: Current advances and perspectives. Bioact Mater 2025; 50:322-343. [PMID: 40276541 PMCID: PMC12020890 DOI: 10.1016/j.bioactmat.2025.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 03/26/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
Recent studies have revealed a great diversity and complexity in extracellular vesicles and particles (EVPs). The developments in techniques and the growing awareness of the particle heterogeneity have spurred active research on new particle subsets. Latest discoveries highlighted unique features and roles of non-vesicular extracellular nanoparticles (NVEPs) as promising biomarkers and targets for diseases. These nanoparticles are distinct from extracellular vesicles (EVs) in terms of their smaller particle sizes and lack of a bilayer membrane structure and they are enriched with diverse bioactive molecules particularly proteins and RNAs, which are widely reported to be delivered and packaged in exosomes. This review is focused on the two recently identified membraneless NVEPs, exomeres and supermeres, to provide an overview of their biogenesis and contents, particularly those bioactive substances linked to their bio-properties. This review also explains the concepts and characteristics of these nanoparticles, to compare them with other EVPs, especially EVs, as well as to discuss their isolation and identification methods, research interests, potential clinical applications and open questions.
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Affiliation(s)
- Li Yu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou, 215600, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Hui Shi
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou, 215600, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang, 212000, Jiangsu, China
- Pharmaceutical Sciences Laboratory, Åbo Akademi University, Turku, 20520, Finland
| | - Tingxin Gao
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou, 215600, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Wenrong Xu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou, 215600, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou, 215600, Jiangsu, China
| | - Xiao Yang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China
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15
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Ma T, Liu Q, Zhang Z, Nan J, Liu G, Yang Y, Hu Y, Xie J. Fused exosomal targeted therapy in periprosthetic osteolysis through regulation of bone metabolic homeostasis. Bioact Mater 2025; 50:171-188. [PMID: 40248188 PMCID: PMC12005309 DOI: 10.1016/j.bioactmat.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 03/18/2025] [Accepted: 04/03/2025] [Indexed: 04/19/2025] Open
Abstract
The onset of periprosthetic osteolysis is mediated by wear particles following artificial arthroplasty. This manifests as a disturbed bone metabolism microenvironment, characterized by insufficient osteogenesis and angiogenesis, and enhanced osteoclastic activity. To target and remodel the homeostatic environment of bone metabolism in the sterile region around the prosthesis, we successfully pioneered the proposal and construction of a fused exosome (f-exo) system with M2 macrophage-derived exosomes (M2-exo) and urine-derived stem cell exosomes (USC-exo). The results demonstrate that f-exo effectively combines the osteolysis region-targeting capabilities of M2-exo with the bone metabolic homeostasis modulation effects of two exosomes (M2-exo and USC-exo), thereby achieving a significantly enhanced bone metabolic homeostasis targeting effect in the periprosthetic osteolysis region. The proteomic analysis of M2-exo, USC-exo, and f-exo revealed the potential mechanism of f-exo in targeting-regulation of bone metabolic homeostasis. Our study employs an innovative approach utilizing the fused exosome system for exosome targeted delivery, which offers a novel intervention strategy for the clinical management of periprosthetic osteolysis. Furthermore, it provides a novel conceptual framework for the development of exosome-based drug-targeting delivery systems.
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Affiliation(s)
| | | | - Zheyu Zhang
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, Zhejiang, 310003, China
| | - Jiangyu Nan
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, Zhejiang, 310003, China
| | - Guanzhi Liu
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, Zhejiang, 310003, China
| | - Yute Yang
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, Zhejiang, 310003, China
| | - Yihe Hu
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, Zhejiang, 310003, China
| | - Jie Xie
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, Zhejiang, 310003, China
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16
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Peng N, Gao X, Yong Z, Zhang Y, Guo X, Wang Q, Wan Y, Zhao S, Zhang T, Hu F. "Sample-in, result-out" liquid biopsy chip based on immunomagnetic separation and CRISPR detection for multiplex analysis of exosomal microRNAs. Biosens Bioelectron 2025; 280:117460. [PMID: 40215698 DOI: 10.1016/j.bios.2025.117460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/07/2025] [Accepted: 04/07/2025] [Indexed: 04/25/2025]
Abstract
Multiplex analysis of exosomal microRNAs (miRNAs) plays an important role in noninvasive early disease diagnosis. However, the complexity of the testing process has hindered its clinical application. Here, we proposed an integrated chip for the detection of eight exosomal miRNAs in serum which can achieve "sample in, result out" detection. We developed an immunomagnetic isolation system based on CD63 aptamers (IISA) for separation of serum exosomes. The system was combined with immiscible filtration assisted by surface tension (IFAST) to remove impurities. Bubble mixing was applied to ensure adequate binding or cleavage of exosomes to magnetic beads. CRISPR detection technology was utilized to allow for effective detection of seven hepatocellular carcinoma (HCC)-related miRNA targets. Based on the test of clinical samples, the chip can achieve 78 % exosome capture efficiency and 55 % recovery, and simultaneously detect eight targets within 1 h. This chip could be applied as a robust and cost-effective tool for cancer diagnosis and monitoring of cancer stages.
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Affiliation(s)
- Niancai Peng
- State Key Laboratory for Manufacturing Systems Engineering, School of Instrument Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China; Xi'an Key Laboratory of Biomedical Testing and High-End Equipment, Xi'an, 710049, Shaanxi, China
| | - Xueqin Gao
- State Key Laboratory for Manufacturing Systems Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Zhang Yong
- State Key Laboratory for Manufacturing Systems Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Yunyun Zhang
- Xi'an Key Laboratory of Biomedical Testing and High-End Equipment, Xi'an, 710049, Shaanxi, China
| | - Xiaoniu Guo
- State Key Laboratory for Manufacturing Systems Engineering, School of Instrument Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Qiaochu Wang
- State Key Laboratory for Manufacturing Systems Engineering, School of Instrument Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Yong Wan
- Department of Geriatric Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Shuhao Zhao
- State Key Laboratory for Manufacturing Systems Engineering, School of Instrument Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Tianyi Zhang
- State Key Laboratory for Manufacturing Systems Engineering, School of Instrument Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Fei Hu
- State Key Laboratory for Manufacturing Systems Engineering, School of Instrument Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
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17
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Zhao Y, Chen L, Jiang S, Wu Z, Xiang Q, Lin J, Tian S, Sun Z, Sun C, Li W. Exosomes derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by alleviating the senescence of nucleus pulposus cells through epigenetic modifications. Bioact Mater 2025; 49:515-530. [PMID: 40206196 PMCID: PMC11979484 DOI: 10.1016/j.bioactmat.2025.02.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 02/11/2025] [Accepted: 02/28/2025] [Indexed: 04/11/2025] Open
Abstract
Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which places heavy burdens on society and individuals. Surgical intervention is the conventional therapy for IDD, but patients who undergo surgery face relatively high risks of recurrence and complications. Therefore, a relatively less invasive and efficient treatment for IDD is urgently needed. In this study, we constructed a novel nanobiomaterial, named Hi-Exos, to slow IDD. Hi-Exos are exosomes derived from mesenchymal stem cells exposed to hypoxic and inflammatory environments. Hi-Exos could relieve the senescence of nucleus pulposus cells and slow IDD through an epigenetic modification mechanism by introducing the epigenetic factor miR-221-3p into senescent nucleus pulposus cells to reduce DDIT4 expression and inhibit the activation of NF-κB signalling pathway. This study provided a novel strategy for IDD treatment involving the use of Hi-Exos to deliver miR-221-3p to reduce the senescence of nucleus pulposus cells and repair IDD via epigenetic modifications.
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Affiliation(s)
- Yongzhao Zhao
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Longting Chen
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Shuai Jiang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Zhenquan Wu
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Qian Xiang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Jialiang Lin
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Shuo Tian
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Zhuoran Sun
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Chuiguo Sun
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
| | - Weishi Li
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
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18
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Ge W, Mu Z, Yang S, Zeng Y, Deng Y, Lin Y, Xie P, Li G. Biosensor-based methods for exosome detection with applications to disease diagnosis. Biosens Bioelectron 2025; 279:117362. [PMID: 40157151 DOI: 10.1016/j.bios.2025.117362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/09/2025] [Accepted: 03/09/2025] [Indexed: 04/01/2025]
Abstract
Exosomes are nanoscale extracellular vesicles (EVs) secreted by most eukaryotic cells and can be found in nearly all human body fluids. Increasing evidence has revealed their pivotal roles in intercellular communication, and their active participation in myriad physiological and pathological activities. Exosomes' functions rely on their contents that are closely correlated with the biological characteristics of parental cells, which may provide a rich resource of molecular information for accurate and detailed diagnosis of a diverse array of diseases, such as differential diagnosis of Alzheimer's disease, early detection and subtyping of various tumors. As a category of sensitive detection devices, biosensors can fully reveal the molecular information and convert them into actionable clinical information. In this review, recent advances in biosensor-based methods for the detection of exosomes are summarized. We have described the fabrication of various biosensors based on the analysis of exosomal proteins, RNAs or glycans for accurate diagnosis, with respect to their elaborate recognition designs, signal amplification strategies, sensing properties, as well as their application potential. The challenges along with corresponding technologies in the future development and clinical translation of these biosensors are also discussed.
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Affiliation(s)
- Weikang Ge
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, People's Republic of China
| | - Zheying Mu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, People's Republic of China
| | - Shiao Yang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, People's Republic of China
| | - Yujing Zeng
- Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China
| | - Ying Deng
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, People's Republic of China
| | - Yifan Lin
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Ping Xie
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China.
| | - Genxi Li
- State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing 210023, People's Republic of China; Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China.
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19
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Nikapitiya C, Jayathilaka EHTT, Edirisinghe SL, Oh C, De Zoysa M. Characterization, microRNA profiling, and immunomodulatory role of plasma-derived exosomes from olive flounder (Paralichthys olivaceus) in response to viral hemorrhagic septicemia virus. FISH & SHELLFISH IMMUNOLOGY 2025; 162:110316. [PMID: 40239934 DOI: 10.1016/j.fsi.2025.110316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 04/02/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025]
Abstract
Viral hemorrhagic septicemia virus (VHSV) is a highly pathogenic virus that frequently infects olive flounder (Paralichthys olivaceus), causing viral hemorrhagic septicemia (VHS), and posing a significant threat to global aquaculture. This study characterizes plasma-derived exosomes from olive flounder following VHSV challenge (VHSV-Exo) or phosphate buffered saline (PBS) injection (PBS-Exo), comparing their morphology, physicochemical properties, molecular profiles, and immunomodulatory functions. Both PBS-Exo (118.3 ± 8.6 nm) and VHSV-Exo (82.6 ± 5.9 nm) exhibited the typical cup-shaped morphology of exosomes. The successful isolation and purity of exosomes were confirmed by the presence of exosome markers (CD81, CD9, and CD63) and the absence of albumin. High-throughput sequencing identified 13 differentially expressed (DE) microRNAs (miRNAs) between PBS-Exo and VHSV-Exo, including six upregulated and seven downregulated miRNAs (log2 fold change ≥1 or ≤ -1). Toxicity assessments revealed that neither PBS-Exo nor VHSV-Exo were toxic to murine macrophage Raw 264.7 cells or zebrafish larvae at tested doses (up to 100 and 400 μg/mL, respectively). The absence of green fluorescence at 96 h post-treatment of VHSV-Exo indicated minimal reactive oxygen species generation, further supporting exosome safety. Functional studies demonstrated that both in vitro (Raw 264.7 cells) and in vivo (adult zebrafish) treatments with exosomes regulated immune-related genes and proteins expression. Notabaly, VHSV-Exo exhibited superior immunomodulatory effects, as evidenced by enhanced immune gene and protein expression. To our knowledge, this is the first study demonstrating the immunomodulatory potential of VHSV-Exo. These findings highlight VHSV-Exo as a promising immunomodulatory agent, with potential applications as a prophylactic vaccine candidate against VHSV infection in aquaculture.
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Affiliation(s)
- Chamilani Nikapitiya
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - E H T Thulshan Jayathilaka
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - Shan Lakmal Edirisinghe
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - Chulhong Oh
- Jeju Bio Research Center, Korea Institute of Ocean Science and Technology, Gujwa-eup, Jeju, 2670, Republic of Korea
| | - Mahanama De Zoysa
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea.
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20
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Chen S, Cheng J, Liu S, Shan D, Wang T, Wang X. Urinary exosomal lnc-TAF12-2:1 promotes bladder cancer progression through the miR-7847-3p/ASB12 regulatory axis. Genes Dis 2025; 12:101384. [PMID: 40297540 PMCID: PMC12036056 DOI: 10.1016/j.gendis.2024.101384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 06/02/2024] [Accepted: 06/22/2024] [Indexed: 04/30/2025] Open
Abstract
Exosomes encompass a great deal of valuable biological information and play a critical role in tumor development. However, the mechanism of exosomal lncRNAs remains poorly elucidated in bladder cancer (BCa). In this study, we identified exosomal lnc-TAF12-2:1 as a novel biomarker in BCa diagnosis and aimed to investigate the underlying biological function. Dual luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pulldown assays, and xenograft mouse model were used to verify the competitive endogenous RNA mechanism of lnc-TAF12-2:1. We found exosomal lnc-TAF12-2:1 up-regulated in urinary exosomes, tumor tissues of patients, and BCa cells. Down-regulation of lnc-TAF12-2:1 impaired BCa cell proliferation and migration, and promoted cell cycle arrest at the G0/G1 phase and cell apoptosis. The opposite effects were also observed when lnc-TAF12-2:1 was overexpressed. lnc-TAF12-2:1 was transferred by intercellular exosomes to modulate malignant biological behavior. Mechanistically, lnc-TAF12-2:1 packaged in the exosomes relieved the miRNA-mediated silence effect on ASB12 via serving as a sponger of miR-7847-3p to accelerate progression in BCa. ASB12 was also first proved as an oncogene to promote cell proliferation and migration and depress cell cycle arrest and cell apoptosis in our data. In conclusion, exosomal lnc-TAF12-2:1, located in the cytoplasm of BCa, might act as a competitive endogenous RNA to competitively bind to miR-7847-3p, and then be involved in miR-7847-3p/ASB12 regulatory axis to promote tumorigenesis, which provided a deeper insight into the molecular mechanism of BCa.
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Affiliation(s)
- Song Chen
- Department of Urology, Zhongnan Hospital of Wuhan University, Institute of Urology, Wuhan University, Wuhan, Hubei 430071, China
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
- Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, Hubei 430071, China
- Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, Hubei 430071, China
| | - Jie Cheng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Shuangtai Liu
- Department of Urology, Zhongnan Hospital of Wuhan University, Institute of Urology, Wuhan University, Wuhan, Hubei 430071, China
| | - Danni Shan
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
- Human Genetic Resources Preservation Center of Hubei Province, Wuhan, Hubei 430071, China
| | - Ting Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Institute of Urology, Wuhan University, Wuhan, Hubei 430071, China
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Institute of Urology, Wuhan University, Wuhan, Hubei 430071, China
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, Hubei 430071, China
- Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, Hubei 430071, China
- TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, Hubei 430071, China
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21
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Kim SH, Kim CH, Lee CH, Lee J, Kang H, Cho S, Jang WH, Park M, Ha M, Kim J, Um W, Kwon S, Lee S, Kim JW, Chung CH, Park JH. Glycoengineered stem cell-derived extracellular vesicles for targeted therapy of acute kidney injury. Biomaterials 2025; 318:123165. [PMID: 39923538 DOI: 10.1016/j.biomaterials.2025.123165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/20/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
Acute kidney injury (AKI) is associated with high morbidity and mortality rates, primarily due to the lack of effective therapeutic options for kidney repair. To restore the biological function of injured kidney, there is a need to protect renal tubular epithelial cells (RTECs) and regulate M1 macrophages, responsible for progress of AKI. Herein, based on metabolic glycoengineering-mediated click chemistry, we prepare the engineered extracellular vesicles (pSEVs), derived from PEGylated hyaluronic acid (HA)-modified mesenchymal stem cells. Owing to their cell-protective and anti-inflammatory properties, pSEVs effectively prevent the apoptosis of RTECs and inhibit the polarization of macrophages into an inflammatory phenotype in vitro. When systemically administered into the cisplatin-induced AKI animal model, pSEVs selectively accumulate in injured kidneys via HA-mediated binding to CD44 and toll-like receptor4 which are over-expressed on RTECs and M1 macrophages, respectively. This targeted delivery efficiently alleviates AKI-related symptoms, as evidenced by delayed kidney weight reduction, and decreased levels of creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin. Overall, pSEVs show potent anti-inflammatory effects and specific targeting to injured kidneys, presenting a considerable potential as the therapeutics for AKI.
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Affiliation(s)
- So Hee Kim
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Chan Ho Kim
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Chang Hyun Lee
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Jungmi Lee
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Heegun Kang
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Sohyun Cho
- Department of MetaBioHealth, SKKU Institute for Convergence, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Won Ho Jang
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Minsung Park
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Minji Ha
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Jiyeon Kim
- Department of MetaBioHealth, SKKU Institute for Convergence, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Wooram Um
- Department of Biotechnology, Pukyong National University, 45 Yongso-ro, Nam-gu, Busan, 48513, Republic of Korea
| | - Seunglee Kwon
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Sangho Lee
- Department of Biological Sciences, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Republic of Korea Suwon, Suwon, 16419, Republic of Korea
| | - Jin Woong Kim
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Chan-Hwa Chung
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea; Department of MetaBioHealth, SKKU Institute for Convergence, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
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22
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Saha T, Mehrotra S, Gupta P, Kumar A. Exosomal miRNA combined with anti-inflammatory hyaluronic acid-based 3D bioprinted hepatic patch promotes metabolic reprogramming in NAFLD-mediated fibrosis. Biomaterials 2025; 318:123140. [PMID: 39892017 DOI: 10.1016/j.biomaterials.2025.123140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/03/2025] [Accepted: 01/23/2025] [Indexed: 02/03/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder, where the underlying molecular mechanisms are mostly not well-understood and therefore, warrants the need for therapeutic interventions targeting several metabolic pathways as a unified response. Of late, promising outcomes have been observed with mesenchymal stem cell-derived exosomes. However, reduced bioavailability due to systemic delivery and the need for repeated fresh isolation hinders their feasibility for clinical applications. In this regard, an 'off-the-shelf' 3D bioprinted hyaluronic acid-based hepatic patch to deliver encapsulated exosomes alone/or with hepatocytes (as dual-therapy) is developed as a holistic approach for ameliorating the disease condition and promoting tissue regeneration. The bioprinted hepatic patch demonstrated sustained and localized release of exosomes (∼82 % in 21 days), and healthy liver tissue-like mechanical properties while being biocompatible and biodegradable. Assessment in NAFLD rat models displayed alleviation of the altered biochemical parameters such as fat deposition, deranged liver functions, disrupted lipid, glucose, and insulin metabolism along with a reduction in localized inflammation, and associated liver fibrosis. The study suggests that a synergistic effect between the miRNA population of released exosomes, cell therapy, and the bioprinted matrix materials is crucial in targeting multiple complex metabolic pathways associated with the severity of the disease.
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Affiliation(s)
- Triya Saha
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India
| | - Shreya Mehrotra
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India.
| | - Purva Gupta
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India
| | - Ashok Kumar
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; The Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre for Nanosciences, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre of Excellence for Materials in Medicine, Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India.
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23
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Li Z, Yu Q, Cui X, Wang Y, Xu R, Lu R, Chen J, Zhou X, Zhang C, Li L, Xu W. Exosomes from young plasma stimulate the osteogenic differentiation and prevent osteoporosis via miR-142-5p. Bioact Mater 2025; 49:502-514. [PMID: 40206195 PMCID: PMC11979483 DOI: 10.1016/j.bioactmat.2025.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 03/14/2025] [Accepted: 03/14/2025] [Indexed: 04/11/2025] Open
Abstract
Osteoporosis (OP) is a multifactorial metabolic bone disorder commonly observed in the elderly, particularly prevalent in postmenopausal women. However, many conventional anti-osteoporosis drugs have undesirable side effects, limiting their long-term use. Here, we demonstrated that exosomes derived from both young and old healthy human plasma, which exhibited similar morphology, could significantly enhance the proliferation and migration of mesenchymal stem cells (MSCs). Furthermore, treatment with these exosomes increased alkaline phosphatase (ALP) activity, enhanced the mineralization of MSCs, and decreased the number of osteoclasts in vitro. When intravenously injected into rats, these exosomes accumulated in bone tissue. In vivo experiments demonstrated that both types of exosomes had a beneficial effect on osteoporosis by facilitating bone formation and suppressing osteoclast differentiation in an ovariectomized (OVX)-induced osteoporotic rat model. Strikingly, exosomes derived from young healthy human plasma exhibited stronger anti-osteoporosis effect. The miRNA sequencing analysis showed that miR-142-5p expression was significantly higher in the exosomes from young healthy adult plasma compared to in exosomes from older controls. Importantly, miR-142-5p overexpression exerted similar pro-osteogenic effects to those of exosomes from young healthy human plasma, while miR-142-5p downregulation had the opposite effect on osteogenic differentiation of MSCs. The anti-osteoporosis effect of exosomes from young healthy adult plasma were reversed upon miR-142-5p inhibition. In addition, ZFPM2 was a potential target of miR-142-5p involved in osteoporosis. Therefore, our study reveals the potential anti-osteoporosis effects of plasma exosomes and their underlying mechanisms, thereby providing an effective therapeutic strategy for clinical treatment of osteoporosis.
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Affiliation(s)
- Zhikun Li
- Department of Orthopedic, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- Department of Orthopedic, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200336, China
| | - Qifeng Yu
- Department of Orthopedic, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- Department of Orthopedic, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200336, China
| | - Xiang Cui
- Department of Orthopedic, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200336, China
| | - Yi Wang
- Department of Orthopedic, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200336, China
| | - Ruijun Xu
- Department of Orthopedic, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200336, China
| | - Renjie Lu
- Department of Orthopedic Surgery, Shanghai Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Jiahao Chen
- Department of Orthopedic Surgery, Shanghai Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xiaohan Zhou
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
| | - Chi Zhang
- Department of Orthopedic Surgery, Shanghai Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Lanya Li
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
| | - Wei Xu
- Department of Orthopedic, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- Department of Orthopedic, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200336, China
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24
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Kong H, Chen X, Lee W, Xie X, Tao Y, Li M. Dual-color fluorescence detection of tumor-derived extracellular vesicles using a specific and serum-stable membrane-fusion approach. Biosens Bioelectron 2025; 278:117302. [PMID: 40101657 DOI: 10.1016/j.bios.2025.117302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/05/2025] [Accepted: 02/21/2025] [Indexed: 03/20/2025]
Abstract
Tumor-derived extracellular vesicles (tEVs), which are essential mediators for cell-to-cell communication during tumorigenesis and tumor development, have demonstrated significant diagnostic potential in cancer liquid biopsy, particularly through biomarkers like membrane proteins and inner microRNAs. However, traditional detection methods such as ELISA and qRT-PCR encounter challenges with low sensitivity and specificity, complex procedures, and high costs. Although emerging biosensors have been developed, these methods are limited to detecting a single type of tEV biomarker, which may result in misdiagnoses due to false-positive or false-negative signals. Herein, we introduce a specific and serum-stable membrane-fusion approach (SSMFA) capable of simultaneously detecting tEV proteins and microRNAs via dual-color fluorescence analysis. In this strategy, the established epithelial cell adhesion molecule (EpCAM) aptamer-modified serum-stable membrane-fusion liposome (AptSMFL) is labeled with fluorescence resonance energy transfer (FRET) dye pairs, which can specifically recognize EpCAM-overexpressed tEVs and induce serum-stable membrane fusion, allowing the quantification of EpCAM protein levels through red fluorescence changes resulting from FRET alterations. Meanwhile, SSMFA facilitates efficient transfection of the CRISPR/Cas13a probe into tEVs to analyze the levels of microRNA-21 (miR-21) in EpCAM-positive tEVs via green fluorescence detection. When tested on serum samples from hepatocellular carcinoma models, the SSMFA exhibited minimal sample volume requirement and rapid assay time (2 h) to effectively achieve accurate quantification of both tEV EpCAM protein and miR-21 levels. Additionally, this dual-biomarker detection method showed a strong correlation with tumor burden and significantly improved cancer diagnostic accuracy (AUC = 0.98), underscoring the potential of SSMFA as a promising tEV-based liquid biopsy assay for cancer diagnosis.
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Affiliation(s)
- Huimin Kong
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaodie Chen
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Weijen Lee
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Xi Xie
- State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou 510006, China.
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, China.
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, China.
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25
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Zhou P, Yu M, Pan Y, Pan W, Li N, Tang B. An Au-Se bond-based fluorescent nanoprobe for thermophoretic aggregation imaging of exosomal miRNAs. Biosens Bioelectron 2025; 278:117354. [PMID: 40086118 DOI: 10.1016/j.bios.2025.117354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/16/2025]
Abstract
Exosomal microRNAs (miRNAs) have recently gained prominence as promising biomarkers for non-invasive lung cancer screening. In this study, we innovatively developed an innovative fluorescent nanoprobe based on stable Au-Se bonds to detect lung cancer-associated miRNAs in exosomes. This nanoprobe integrates gold nanoparticles with selenated DNA molecular beacons (MBs) conjugated via 1,4-phenyldiisothiocyanate (PDITC). It demonstrates exceptional stability in high-thiol environments, making it ideal for high-fidelity imaging and biomarker detection in biological settings. By integrating molecular beacons that specifically recognize and bind to target exosomal miRNAs, the nanoprobe enables precise detection. Thermophoretic aggregation imaging of exosomes was achieved using confocal fluorescence microscopy with 1064 nm laser irradiation. Our findings demonstrate that this nanoprobe efficiently identifies lung cancer-related miRNAs in exosomes, providing a promising candidate for early lung cancer detection in clinical applications.
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Affiliation(s)
- Ping Zhou
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Mengyao Yu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Yingbo Pan
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Wei Pan
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China
| | - Na Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China.
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, PR China; Laoshan Laboratory, Qingdao, 266237, PR China.
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26
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Chen ZQ, Tang TT, Tang RN, Zhang Y, Zhang YL, Yang HB, Song J, Yang Q, Qin SF, Chen F, Zhang YX, Wang YJ, Wang B, Lv LL, Liu BC. A comprehensive evaluation of stability and safety for HEK293F-derived extracellular vesicles as promising drug delivery vehicles. J Control Release 2025; 382:113673. [PMID: 40169120 DOI: 10.1016/j.jconrel.2025.113673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/24/2025] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
HEK293F-derived extracellular vesicles (HEK293F-EVs) have great potential as next-generation drug delivery vehicles. A comprehensive understanding of their batch stability and in vivo safety is prerequisite for clinical translation. HEK293F-EVs were purified using ultracentrifugation combined with size exclusion chromatography, and their physicochemical properties, such as morphology, size distribution, and biomarkers, were thoroughly characterized. Raman spectroscopy and multi-omics analyses were employed to elaborate their molecular composition. Blood kinetics and biodistribution were assessed via IVIS spectrum imaging. Additionally, long-term in vivo safety was evaluated following multiple-dose administration through hematology, serum biochemistry, cytokine/chemokine profiling, and histopathology. HEK293F-EVs exhibited stable yields, purity, physicochemical properties (morphology, size, zeta potential, and marker proteins), and chemical composition across different cell passages (P10, P20, P30), with no significant variations. Content profiling, including protein, miRNA, metabolite, and lipid, confirmed consistent molecular stability across five production batches. GO, Reactome, and KEGG analyses revealed minimal enrichment in pathways related to acute immune response or cytotoxicity. Blood kinetics studies indicated rapid clearance of HEK293F-EVs from circulation, though slightly slower than PEG-Liposomes. Organ biodistribution was comparable between HEK293F-EVs and PEG-Liposomes, with HEK293F-EVs potentially having longer retention times. Importantly, HEK293F-EVs exhibited a favorable preclinical long-term safety profile, showing low immunogenicity and fewer tissue lesions compared to PEG-Liposomes. Our study demonstrates that HEK293F-EVs maintain stable physicochemical characteristics and compositions across batches and possess a superior safety profile, suggesting their significant potential as a safe and reliable drug delivery platform for clinical applications.
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Affiliation(s)
- Zhi-Qing Chen
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Tao-Tao Tang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
| | - Ri-Ning Tang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Yue Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Yi-Lin Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Hong-Bin Yang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Jing Song
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Qin Yang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Suo-Fu Qin
- Shenzhen Kexing Pharmaceutical Co., Ltd., Shenzhen, China
| | - Feng Chen
- School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yu-Xia Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Yu-Jia Wang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Bin Wang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Lin-Li Lv
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
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Tang S, Feng K, Yang R, Cheng Y, Shi N, Zhang H, Wei Z, Ma Y. A dual-action strategy: Wound microenvironment responsive hydrogel and exosome-mediated glucose regulation enhance inside-out diabetic wound repair. J Control Release 2025; 382:113716. [PMID: 40210123 DOI: 10.1016/j.jconrel.2025.113716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 03/26/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
Sustained hyperglycemia induces complex pathological microenvironment in diabetic wounds, significantly hindering wound healing. Most current therapeutic approaches (e.g., hydrogel dressings) have paid little attention to the effect of blood glucose levels on diabetic wound healing. In this study, a synergetic therapeutic strategy including a wound microenvironment responsive, multifunctional hydrogel and the exosome-mediated glucose regulation is developed for diabetic wound treatment. First, a gelatin-dopamine (Gel-DA) crosslinked hyaluronic acid-phenylboronic acid (HA-PBA) hydrogel (GDHP) is constructed with good injectable, self-healing, and adhesive abilities. Such GDHP hydrogel not only can effectively relieve oxidative stress and reduce inflammation, but also promote keratinocyte migration. Then, ciprofloxacin hydrochloride (CIP·H) is loaded to prepare the GDHPC hydrogel that may respond to diabetic wound microenvironment (e.g., low pH, high glucose and reactive oxygen species) and degrade for controlled release of CIP·H, showing on-demand antibacterial properties. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-exos) are administered via tail vein injection in diabetic mice, which may repair injured pancreatic islets by modulating the pancreatic immune microenvironment, thus promoting insulin secretion and further reducing blood glucose levels. By applying this synergetic therapeutic strategy, the full-thickness cutaneous wounds in type 1 diabetic mice heal well and quickly compared to that treated with the GDHPC hydrogel and the hucMSC-exos alone. This promotion effect on wound healing may associate with reducing inflammation and promoting angiogenesis. This study sheds new light on the development of a dual-action strategy that can effectively maintain glucose homeostasis, improve the wound microenvironment, and consequently promote inside-out repair of diabetic wounds, offering a promising therapeutic avenue for future diabetic wound treatment.
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Affiliation(s)
- Shaoxin Tang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Keru Feng
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Rui Yang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Yang Cheng
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Nianyuan Shi
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Key Laboratory of Magnetic Medicine, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Hui Zhang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Zhao Wei
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China.
| | - Yufei Ma
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China.
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28
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Han Z, Huang H, Li B, Zhao R, Wang Q, Liu H, Xue H, Zhou W, Li G. Engineering exosome membrane disguised thermal responsive system for targeted drug delivery and controlled release across the blood-brain barrier. Mater Today Bio 2025; 32:101656. [PMID: 40160247 PMCID: PMC11953974 DOI: 10.1016/j.mtbio.2025.101656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 02/02/2025] [Accepted: 03/10/2025] [Indexed: 04/02/2025] Open
Abstract
The blood-brain barrier (BBB) presents a significant challenge for the delivery of chemotherapy drugs to brain tumors, leading to ineffective drug concentrations at the tumor site and contributing to chemotherapy resistance. The hypoxic tumor microenvironment further complicates this process, ultimately resulting in poor patient prognosis. In this study, we developed a thermoresponsive nanocarrier system that incorporates (Ru)(Pt) bimetallic nanoparticles onto defective TiOx nanoparticles with abundant oxygen vacancies, generating composite Ru/Pt-TiOx nanoparticles with photothermal and photocatalytic properties. The Ru and Pt in the nanoparticles enhance the metal-carrier interactions, with Ru increasing both light absorption and photothermal conversion efficiency and Pt catalyzing the conversion of endogenous H2O2 in tumors to produce oxygen. The oxygen produced within the tumor microenvironment reduces HIF-1α, MDR1 and P-gp expression, thereby inhibiting efflux and allowing doxorubicin to accumulate inside the cells. DOX was incorporated into a phase change material and combined with multiple Ru/Pt-TiOx nanoparticles to form composite RPTiOx-DOX particles that can control the release of DOX under near-infrared irradiation. In an effort to overcome the blocking effect of the BBB, we wrapped the RPTiOx-DOX nanoparticles with Angiopep-2-functionalized macrophage exosome membranes. Furthermore, the changes in the internal environment promote macrophage phenotypic transformation (M2→M1) to some extent and further inhibit tumor growth via immunoregulation. In this work, a novel drug delivery system capable of traversing the BBB and exerting synergistic antitumor effects through photostimulated therapeutic agents is described, providing innovative insights for the development of stimulus-responsive composite nanoparticle drug formulations.
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Affiliation(s)
- Zhe Han
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, 250012, China
- Institute of Brain and Brain-Inspired Science, Ji'nan, Shandong, 250012, China
- Shandong Key Laboratory of Brain Function Remodeling, Ji'nan, Shandong, 250012, China
| | - Haina Huang
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Ji'nan, 250022, China
| | - Boyan Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, 250012, China
- Institute of Brain and Brain-Inspired Science, Ji'nan, Shandong, 250012, China
- Shandong Key Laboratory of Brain Function Remodeling, Ji'nan, Shandong, 250012, China
| | - RongRong Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, 250012, China
- Institute of Brain and Brain-Inspired Science, Ji'nan, Shandong, 250012, China
- Shandong Key Laboratory of Brain Function Remodeling, Ji'nan, Shandong, 250012, China
| | - Qingtong Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, 250012, China
- Institute of Brain and Brain-Inspired Science, Ji'nan, Shandong, 250012, China
- Shandong Key Laboratory of Brain Function Remodeling, Ji'nan, Shandong, 250012, China
| | - Hong Liu
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Ji'nan, 250022, China
- State Key Laboratory of Crystal Materials, Shandong University, Ji'nan, 250100, China
| | - Hao Xue
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, 250012, China
- Institute of Brain and Brain-Inspired Science, Ji'nan, Shandong, 250012, China
- Shandong Key Laboratory of Brain Function Remodeling, Ji'nan, Shandong, 250012, China
| | - Weijia Zhou
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Ji'nan, 250022, China
| | - Gang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, 250012, China
- Institute of Brain and Brain-Inspired Science, Ji'nan, Shandong, 250012, China
- Shandong Key Laboratory of Brain Function Remodeling, Ji'nan, Shandong, 250012, China
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Huang J, Chen L, Li W, Chang CJ. Anti-inflammatory and antioxidative effects of Perilla frutescens-derived extracellular vesicles: Insights from Zebrafish models. Mol Immunol 2025; 182:126-138. [PMID: 40267772 DOI: 10.1016/j.molimm.2025.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 04/25/2025]
Abstract
Plant-derived extracellular vesicles have recently been extracted and recognized as promising bioactive molecules, owing to their distinctive biological properties and inherent therapeutic activities. In this study, we investigated the physicochemical characteristics, bioactive properties, and therapeutic potential of Perilla frutescens-derived exosome-like nanoparticles (PELNs). Transmission electron microscopy (TEM) revealed that PELNs exhibited a cup-shaped morphology, with a lipid bilayer and a size distribution ranging from 40 to 200 nm (mean: 68.4 ± 13.0 nm). The cargoes in PELNs were analyzed through multi-omics and small RNA sequencing. In vivo studies on zebrafish demonstrated that PELNs are non-toxic at experimental concentrations. A reduction in neutrophil migration to injured fins evidenced the anti-inflammatory properties of PELNs. Furthermore, a meta-analysis of transcriptomic data identified hundreds of differentially expressed genes (DEGs) across 12 samples of three experimental groups. These DEGs were annotated into three categories following gene ontology (GO) enrichment analysis. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these DEGs were involved in immune-related pathways, including complement and coagulation cascades, systemic lupus erythematosus, PPAR signaling pathways, and antigen processing and presentation. Twelve selected DEGs were validated by quantitative real-time PCR (qRT-PCR), with particular confirmation of the mpx and lcp1 genes via in situ hybridization. Furthermore, PELNs demonstrated antioxidative effects by mitigating reactive oxygen species (ROS) levels, as evidenced by measurements of four oxidative stress (OS) indicators (i.e., SOD, CAT, GSH, and MDA) in zebrafish larvae subjected to H2O2-induced OS. In summary, PELNs exhibit substantial anti-inflammatory and antioxidant properties, underscoring their potential as therapeutic agents for treating various inflammatory diseases.
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Affiliation(s)
- Jinghong Huang
- Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Xiamen, Fujian 362021, China; School of Medicine, Huaqiao University, Quanzhou, Fujian 362021, China
| | - Linxin Chen
- Department of Traditional Chinese Medicine, Xiamen Chang Gung Hospital, Xiamen, Fujian 301028, China
| | - Wenhua Li
- Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Xiamen, Fujian 362021, China; School of Medicine, Huaqiao University, Quanzhou, Fujian 362021, China.
| | - Chih-Jung Chang
- School of Medicine, Huaqiao University, Quanzhou, Fujian 362021, China; Medical Research Center, Xiamen Chang Gung Hospital, Xiamen, Fujian 301028, China; Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, Fujian 301028, China.
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30
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Ye J, Duan C, Han J, Chen J, Sun N, Li Y, Yuan T, Peng D. Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder. Neural Regen Res 2025; 20:1541-1554. [PMID: 38934398 PMCID: PMC11688552 DOI: 10.4103/nrr.nrr-d-23-01878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/09/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.
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Affiliation(s)
- Jinmei Ye
- Division of Mood Disorder, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cong Duan
- Division of Mood Disorder, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaxin Han
- Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Jinrong Chen
- Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Ning Sun
- Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Yuan Li
- Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tifei Yuan
- Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Daihui Peng
- Division of Mood Disorder, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Bian Z, Zhai Y, Zhang Y, Wang T, Li H, Ouyang J, Liu C, Wang S, Hu Z, Chang X, Zhang C, Liu M, Li C. Senescent cartilage endplate stem cells-derived exosomes induce oxidative stress injury in nucleus pulposus cells and aggravate intervertebral disc degeneration by regulating FOXO3. Free Radic Biol Med 2025; 233:39-54. [PMID: 40118349 DOI: 10.1016/j.freeradbiomed.2025.03.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 03/15/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025]
Abstract
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and associated disability worldwide. The cartilage endplate (CEP) is a critical structure in maintaining the homeostasis of the intervertebral disc, by exosomes (Exos)-mediated intracellular communication between cartilage endplate stem cells (CESCs) and nucleus pulposus cells (NPCs). However, whether the senescence of CESCs influences the functionality of CESCs-derived Exos (CESCs-Exos) and participates in the progress of IVDD remains unclear. In this study, we explored the role and mechanism of the Exos-based intracellular communication between senescent CESCs and NPCs in IVDD. CESCs isolated from aged individuals (S-CESCs) exhibited high levels of senescence compared with CESCs isolated from young individuals (Y-CESCs). Exos from Y-CESCs (Y-Exos) and from S-CESCs (S-Exos) were extracted and identified. Surprisingly, we found that S-Exos lost the therapeutic effects as the Y-Exos exhibited in mitigating IVDD, and even aggravated IVDD by inducing oxidative stress injury in NPCs. MicroRNA-sequencing revealed significant upregulation of miR-29b-3p expression in S-Exos. Through microRNA target prediction, dual luciferase assays, RNA-sequencing, lentivirus-mediated overexpression and suppression, we demonstrated that miR-29b-3p regulates the expression of FOXO3 and downstream antioxidant enzymes to induce oxidative stress injury in NPCs. In vivo experiments further verified that countering miR-29b-3p by antagomir reversed the detrimental effects of S-Exos in exacerbating IVDD. This work elucidates the role and mechanism of senescent CESCs in disrupting redox homeostasis in the nucleus pulposus and exacerbating IVDD by Exos-mediated intracellular communication and offers an experimental foundation for the selection of proper CESCs-Exos to obtain better therapeutic effects in IVDD.
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Affiliation(s)
- Zhiqun Bian
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Yu Zhai
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China.
| | - Yuyao Zhang
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Tianling Wang
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Hao Li
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Jian Ouyang
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Chao Liu
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Siya Wang
- College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Zhilei Hu
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Xian Chang
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China
| | - Chao Zhang
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China.
| | - Minghan Liu
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China; State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, 400038, China.
| | - Changqing Li
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Chongqing, 400038, China; State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, 400038, China.
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Jafari N, Zolfi Gol A, Shahabi Rabori V, Saberiyan M. Exploring the role of exosomal and non-exosomal non-coding RNAs in Kawasaki disease: Implications for diagnosis and therapeutic strategies against coronary artery aneurysms. Biochem Biophys Rep 2025; 42:101970. [PMID: 40124995 PMCID: PMC11930191 DOI: 10.1016/j.bbrep.2025.101970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/19/2025] [Accepted: 03/03/2025] [Indexed: 03/25/2025] Open
Abstract
Kawasaki disease (KD) is an acute vasculitis primarily affecting children, with a potential risk of developing coronary artery aneurysms (CAAs) and cardiovascular complications. The emergence of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has provided insights into Kawasaki disease pathogenesis and opened new avenues for diagnosis and therapeutic intervention. Furthermore, polymorphism analysis of ncRNA genes offers significant insights into genetic predisposition to Kawasaki disease, facilitating tailored treatment approaches and risk assessment to improve patient outcomes. Exosomal ncRNAs, which are ncRNAs encapsulated within extracellular vesicles, have garnered significant attention as potential biomarkers for Kawasaki disease and CAA due to their stability and accessibility in biological fluids. This review comprehensively discusses the biogenesis, components, and potential of exosomal and non-exosomal ncRNAs in Kawasaki disease diagnosis and prognosis prediction. It also highlights the roles of non-exosomal ncRNAs, such as miRNAs, lncRNAs, and circRNAs, in Kawasaki disease pathogenesis and their implications as therapeutic targets. Additionally, the review explores the current diagnostic and therapeutic approaches for Kawasaki disease and emphasizes the need for further research to validate these ncRNA-based biomarkers in diverse populations and clinical settings.
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Affiliation(s)
- Negar Jafari
- Department of Cardiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ali Zolfi Gol
- Department of Cardiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Venus Shahabi Rabori
- Department of Cardiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammadreza Saberiyan
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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Lu Z, Lyu Z, Dong P, Liu Y, Huang L. N6-methyladenosine RNA modification in stomach carcinoma: Novel insights into mechanisms and implications for diagnosis and treatment. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167793. [PMID: 40088577 DOI: 10.1016/j.bbadis.2025.167793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 02/16/2025] [Accepted: 03/03/2025] [Indexed: 03/17/2025]
Abstract
N6-methyladenosine (m6A) RNA methylation is crucially involved in the genesis and advancement of gastric cancer (GC) by controlling various pathobiological aspects including gene expression, signal transduction, metabolism, cell death, epithelial-mesenchymal transition, angiogenesis, and exosome function. Despite its importance, the exact mechanisms by which m6A modification influences GC biology remain inadequately explored. This review consolidates the latest advances in uncovering the mechanisms and diverse roles of m6A in GC and proposes new research and translational directions. Key regulators (writers, readers, and erasers) of m6A, such as METTL3/14/16 and WTAP, significantly affect cancer progression, anticancer immune response, and treatment outcomes. m6A modification also impacts immune cell infiltration and the tumor microenvironment, highlighting its potential as a diagnostic and prognostic marker. Interactions between m6A methylation and non-coding RNAs offer further novel insights into GC development and therapeutic targets. Targeting m6A regulators could enhance immunotherapy response, overcome treatment resistance, and improve oncological and clinical outcomes. Models based on m6A can precisely predict treatment response and prognosis in GC. Additional investigation is needed to fully understand the mechanisms of m6A methylation and its potential clinical applications and relevance (e.g., as precise markers for early detection, prediction of outcome, and response to therapy and as therapeutic targets) in GC. Future research should focus on in vivo studies, potential clinical trials, and the examination of m6A modification in other types of cancers.
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Affiliation(s)
- Zhengmao Lu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Zhaojie Lyu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Yunmei Liu
- School of Cultural Heritage and Information Management, Shanghai University, Shanghai, China.
| | - Lei Huang
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, Shanghai Institute of Pancreatic Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai 200433, China; National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai 200433, China.
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Xiang Y, Liu Q, Liu K, Chen L, Chen F, Li T, Li S, Yu Q, Lv Q, Xiang Z. An exosome-based nanoplatform for siRNA delivery combined with starvation therapy promotes tumor cell death through autophagy, overcoming refractory KRAS-mutated tumors and restoring cetuximab chemosensitivity. Mater Today Bio 2025; 32:101732. [PMID: 40290881 PMCID: PMC12022660 DOI: 10.1016/j.mtbio.2025.101732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 04/01/2025] [Accepted: 04/04/2025] [Indexed: 04/30/2025] Open
Abstract
Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant results. Artificial vectors are emerging as promising delivery systemts for RNA for gene therapy. In this study, a multi-drug therapy system was built based on a biodegradable exosome nano-platform exploiting the protective and low immunogenic properties of exosomes for RNA. This work aimed to accomplish the co-delivery of siRNA and 3-Bromopyruvic acid (3BP) on an exosome nanoplatform, enhancing targeting by coupling cetuximab (CTX) to exosome membranes, resulting in a new nanomedicine Exo@siRNA/3BP-CTX (ERBC) engineered exosomes. The synthesis conditions were optimized to obtain stable, safe, and effective nanomedicines. Successful targeting of tumors with CTX inhibited KRAS oncogene expression and significantly reduced glucose uptake by cancer cells. This enhanced the starvation therapy effect of the energy deprivation agent 3BP, thus promoting excessive autophagy activation in cells and doubling apoptosis. However, ERBC combined with CTX therapy restored cellular chemosensitivity to CTX. These findings indicate that engineered exosomes with dual therapeutic activities is a promising approach for treating refractory KRAS-mutant cancers.
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Affiliation(s)
- Yurong Xiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
- Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
| | - Qiang Liu
- Department of Hepatobiliary Surgery, Suining First People's Hospital, 22 Youfang Street, 629000, Suining, China
| | - Kang Liu
- Department of Cardiovascular Surgery, Fuwai Yunnan Cardiovascular Hospital, 528 Shahe North Road, 400042, Kunming, China
| | - Liuxian Chen
- Department of Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, No.1 Medical College Road, 400016, Chongqing, China
| | - Fengjiao Chen
- Center for Clinical Molecular Medical Detection and Biobank, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
| | - Tao Li
- Department of Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, No.1 Medical College Road, 400016, Chongqing, China
| | - Siqi Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
- Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
| | - Qiang Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
- Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
| | - Quan Lv
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
- Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
| | - Zheng Xiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
- Chongqing Key Laboratory of Department of General Surgery, The First Afiliated Hospital of Chongqing Medical University, No.1 Youyi Road, 400000, Chongqing, China
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Goyal A, Afzal M, Goyal K, Ganesan S, Kumari M, Sunitha S, Dash A, Saini S, Rana M, Gupta G, Ali H, Wong LS, Kumarasamy V, Subramaniyan V. MSC-derived extracellular vesicles: Precision miRNA delivery for overcoming cancer therapy resistance. Regen Ther 2025; 29:303-318. [PMID: 40237010 PMCID: PMC11999318 DOI: 10.1016/j.reth.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/04/2025] [Accepted: 03/18/2025] [Indexed: 04/17/2025] Open
Abstract
Cancer remains a prominent worldwide health concern, presenting existing therapies with frequent difficulties, including major toxicity, limited effectiveness, and treatment resistance emergence. These issues highlight the necessity for novel and enhanced remedies. Exosomes, tiny extracellular vesicles that facilitate intercellular communication, have attracted interest for their potential medicinal applications. Carrying a variety of molecules, including microRNAs, small interfering RNAs, long non-coding RNAs, proteins, lipids, and DNA, these vesicles are positioned as promising cancer treatment options. Current studies have increasingly investigated the capacity of microRNAs as a strategic approach for combating malignancy. Mesenchymal stem cells (MSC) are recognized for their aptitude to augment blood vessel formation, safeguard against cellular death, and modulate immune responses. Consequently, researchers examine exosomes derived from MSCs as a safer, non-cellular choice over therapies employing MSCs, which risk undesirable differentiation. The focus is shifting towards employing miRNA-encapsulated exosomes sourced from MSCs to target and heal cancerous cells selectively. However, the exact functions of miRNAs within MSC-derived exosomes in the context of cancer are still not fully understood. Additional exploration is necessary to clarify the role of these miRNAs in malignancy progression and to pinpoint viable therapeutic targets. This review offers a comprehensive examination of exosomes derived from mesenchymal stem cells, focusing on the encapsulation of miRNAs, methods for enhancing cellular uptake and stability, and their potential applications in cancer treatment. It also addresses the difficulties linked to this methodology and considers future avenues, including insights from current clinical oncology research.
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Affiliation(s)
- Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - S. Sunitha
- Department of CHEMISTRY, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Aniruddh Dash
- Department of Orthopaedics IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751030, India
| | - Suman Saini
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
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Merhej T, El Fekih R, Azzi JR. Urinary biomarkers of kidney transplant rejection. Curr Opin Organ Transplant 2025; 30:195-200. [PMID: 40173008 DOI: 10.1097/mot.0000000000001217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
PURPOSE OF REVIEW Despite the introduction of many new immunosuppressive medications, allograft rejection remains a significant complication in transplantation. The use of "liquid biopsy" to evaluate allograft function and detect early rejection has recently become a prominent focus of investigation as it holds promise in providing noninvasive and immediate insights into the cellular and molecular makeup of the graft. RECENT FINDINGS In recent years, the introduction of molecular medicine along with the use of new technologies, including high-throughput techniques, has not only accelerated biomarker discovery but has also contributed to improving our understanding of the mechanisms underlying immune rejection. Genomics, transcriptomics, and metabolomics approaches, along with the increasing use of machine learning techniques, have paved the way for the discovery and development of novel biomarkers. SUMMARY Each year, there are hundreds of new biomarker discoveries in the publications. However, only a small fraction can be practically used as clinical tests or surrogate endpoints, receive FDA approval, and reach clinical application. Well designed and reproducible discovery and validation studies are rare and crucial. A contributing factor could be poor study design or quality of biospecimen repositories. In this review, we discuss urinary biomarkers of kidney allograft rejection that have shown promising findings but have yet to be successfully transitioned from bench to bedside.
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Affiliation(s)
- Tamara Merhej
- Renal Division, Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Atabay M, Inci F, Saylan Y. Computational studies for the development of extracellular vesicle-based biosensors. Biosens Bioelectron 2025; 277:117275. [PMID: 39999607 DOI: 10.1016/j.bios.2025.117275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 12/25/2024] [Accepted: 02/14/2025] [Indexed: 02/27/2025]
Abstract
Cancer affects millions of people, and early detection and efficient treatment are two strong levers to hurdle this disease. Recent studies on exosomes, a subset of extracellular vesicles, have deliberately shown the potential to function as a biomarker or treatment tool, thereby attracting the attention of researchers who work on developing biosensors. Due to the ability of computational methods to predict of the behavior of biomolecules, the combination of experimental and computational methods would enhance the analytical performance of the biosensor, including sensitivity, accuracy, and specificity, even detecting such vesicles from bodily fluids. In this regard, the role of computational methods such as molecular docking, molecular dynamics simulation, and density functional theory is overviewed in the development of biosensors. This review highlights the investigations and studies that have been reported using these methods to design exosome-based biosensors. This review concludes with the role of the quantum mechanics/molecular mechanics method in the investigation of chemical processes of biomolecular systems and the deficiencies in using this approach to develop exosome-based biosensors. In addition, the artificial intelligence theory is explained briefly to show its importance in the study of these biosensors.
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Affiliation(s)
- Maryam Atabay
- UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, Turkey; Department of Chemistry, Hacettepe University, Ankara, Turkey
| | - Fatih Inci
- UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, Turkey; Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey
| | - Yeşeren Saylan
- Department of Chemistry, Hacettepe University, Ankara, Turkey.
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Jin P, Bai X. Exploring the roles and clinical potential of exosome-derived non-coding RNAs in glioma. IBRO Neurosci Rep 2025; 18:323-337. [PMID: 40034544 PMCID: PMC11872630 DOI: 10.1016/j.ibneur.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 01/17/2025] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Non-coding accounts for 98 %-99 % of the human genome and performs many essential regulatory functions in eukaryotes, involved in cancer development and development. Non-coding RNAs are abundantly enriched in exosomes, which play a biological role as vectors. Some biofunctional non-coding RNAs are specifically designed as exosomes for the treatment of cancers such as glioma. Glioma is one of the most common primary tumors within the skull and has varying degrees of malignancy and histologic subtypes of grades I-IV. Gliomas are characterized by high malignancy and an abundant blood supply due to rapid cell proliferation and vascularization, often with a poor prognosis. Exosomal non-coding RNAs can be involved in the tumorigenesis process of glioma from multiple directions, such as angiogenesis, tumor proliferation, metastatic invasion, immune evasion, apoptosis, and autophagy. Therefore, non-coding RNAs in exosomes are suitable as markers or therapeutic targets for early diagnosis of diseases and for predicting the prognosis of a variety of diseases. Regulating exosome production and the level of exosomal non-coding RNA expression may be a new approach to prevent or eliminate glioma. In this review, we review the origin and characteristics of exosomal non-coding RNAs, and introduce the functional studies of exosomal non-coding RNAs in glioma and their potential clinical applications, in order to broaden new ideas for the treatment of glioma.
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Affiliation(s)
- Peng Jin
- Department of Neurosurgery, Hulunbuir People’s Hospital, Hulunbuir, Inner Mongolia Autonomous Region 021000, China
| | - Xue Bai
- Department of Intensive Care Unit, Hulunbuir People’s Hospital, No. 20, Shengli Street, Hailar District, Hulunbuir, Inner Mongolia Autonomous Region 021000, China
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Zhu Y, Liu Y, Yang K, Wu W, Cheng Y, Ding Y, Gu R, Liu H, Zhang X, Liu Y. Apoptotic vesicles inhibit bone marrow adiposity via wnt/β-catenin signaling. Regen Ther 2025; 29:262-270. [PMID: 40230357 PMCID: PMC11994938 DOI: 10.1016/j.reth.2025.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 02/14/2025] [Accepted: 03/18/2025] [Indexed: 04/16/2025] Open
Abstract
Background There is currently increasing focus on aging-related diseases. Osteoporosis is a common disease the incidence of which increases with age. In older patients with osteoporosis, bone marrow mesenchymal stem cells (BMMSCs) have a decreased capacity for osteogenesis and an increased capacity for adipogenesis, causing excessive accumulation of adipose tissue in the bone marrow. Therefore, means of reducing bone marrow adiposity may have therapeutic potential for osteoporosis. Apoptotic vesicles (apoVs) participate in a wide range of physiological processes and have been shown to have therapeutic effects in a variety of diseases. The principal objective of this study was to examine the special properties and regulatory mechanisms of BMMSC-derived apoVs in the treatment of bone marrow adiposity. Results The results showed that apoVs could decrease bone marrow adiposity in osteoporotic mice and prevent adipogenic differentiation of MSCs by activating the Wnt/β-catenin pathway. Conclusion New apoV-based therapies have potential for the treatment of bone marrow adiposity in patients with aging-related osteoporosis and may be further applicable to the treatment of obesity and aging-related diseases.
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Affiliation(s)
- Yuan Zhu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
- Department of Stomatology, Peking University Third Hospital, Beijing 100191, China
| | - Yaoshan Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
| | - Kunkun Yang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
| | - Weiliang Wu
- School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350002, China
| | - Yawen Cheng
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
| | - Yanan Ding
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
| | - Ranli Gu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
| | - Hao Liu
- The Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
- National Center of Stomatology, National Laboratory for Digital and Material Technology of Stomatology, National Clinical Research Center for Oral Diseases, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Xiao Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
- National Center of Stomatology, National Laboratory for Digital and Material Technology of Stomatology, National Clinical Research Center for Oral Diseases, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Yunsong Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing 100081, China
- National Center of Stomatology, National Laboratory for Digital and Material Technology of Stomatology, National Clinical Research Center for Oral Diseases, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing 100081, China
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Chen H, Pang B, Liu Z, Li B, Wang Q, Fan B, Han M, Gong J, Zhou C, Chen Y, Li Y, Jiang J. The Diagnostic Value of Plasma Small Extracellular Vesicle-Derived CAIX Protein in Prostate Cancer and Clinically Significant Prostate Cancer: A Study on Predictive Models. Prostate 2025; 85:723-741. [PMID: 40013658 PMCID: PMC12038087 DOI: 10.1002/pros.24879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 01/25/2025] [Accepted: 02/14/2025] [Indexed: 02/28/2025]
Abstract
BACKGROUND Current diagnostic tools are inaccurate and not specific to prostate cancer (PCa) diagnosis. Cancer-derived small extracellular vehicles (sEVs) play a key role in intercellular communication. In this study, we examined the diagnostic value of plasma sEV-derived carbonic anhydrase IX (CAIX) protein for PCa and clinically significant prostate cancer (csPCa) diagnosis and avoiding unnecessary biopsies. METHODS Plasma samples (n = 230) were collected from the patients who underwent prostate biopsy with elevated prostate-specific antigen (PSA) levels. sEVs were isolated and characterized, and sEV protein CAIX was measured using an enzyme-linked immunosorbent assay. Independent predictors of csPCa (Gleason score ≥ 7) were identified, and a predictive model was established. A Nomogram for predicting csPCa was developed using data from the training cohort. RESULTS The expression of sEV protein CAIX was significantly higher in both PCa and csPCa compared to benign patients and nonsignificant PCa (nsPCa) (Gleason score < 7, p < 0.001). sEV protein CAIX performed well in distinguishing PCa from benign patients. The predictive model defined by sEV protein CAIX and PSA density (PSAD) demonstrated the highest discriminative ability for csPCa (AUC = 0.895), with diagnostic sensitivity and specificity of 82.5% and 85.8%, respectively. Furthermore, sEV protein CAIX is an effective predictor of 2-year biochemical recurrence (BCR) in PCa patients (p = 0.013), and its high expression is significantly associated with poorer BCR-free survival (p < 0.05). CONCLUSIONS Our findings demonstrate the excellent performance of sEV protein CAIX in PCa and csPCa diagnosis. The Nomogram-based csPCa predictive model incorporating sEV protein CAIX and PSAD exhibits strong predictive value. Additionally, assessing plasma sEV protein CAIX expression levels can further aid in evaluating patient prognosis and provide a basis for making effective treatment decisions.
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Affiliation(s)
- Haotian Chen
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Bairen Pang
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Zhejiang Engineering Research Center of Innovative Technologies and Diagnostic and Therapeutic Equipment for Urinary System DiseasesNingboZhejiangChina
| | - Zhihan Liu
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Benjie Li
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Qi Wang
- Cancer Care Centre, St George HospitalKogarahNew South WalesAustralia
- St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW SydneyKensingtonNew South WalesAustralia
| | - Baokun Fan
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Meng Han
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Zhejiang Engineering Research Center of Innovative Technologies and Diagnostic and Therapeutic Equipment for Urinary System DiseasesNingboZhejiangChina
| | - Jie Gong
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Cheng Zhou
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Zhejiang Engineering Research Center of Innovative Technologies and Diagnostic and Therapeutic Equipment for Urinary System DiseasesNingboZhejiangChina
| | - Yingzhi Chen
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Yong Li
- Cancer Care Centre, St George HospitalKogarahNew South WalesAustralia
- St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW SydneyKensingtonNew South WalesAustralia
| | - Junhui Jiang
- The First Affiliated Hospital of Ningbo University, Health Science CenterNingbo UniversityNingboZhejiangChina
- Ningbo Clinical Research Center for Urological DiseaseThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Translational Research Laboratory for Urology, Department of UrologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Zhejiang Engineering Research Center of Innovative Technologies and Diagnostic and Therapeutic Equipment for Urinary System DiseasesNingboZhejiangChina
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Zhang H, Jiang N, Xu M, Jing D, Dong T, Liu Q, Lv Q, Huo R, Chen P, Li L, Wang X. M2 macrophage derived exosomal miR-20a-5p ameliorates trophoblast pyroptosis and placental injuries in obstetric antiphospholipid syndrome via the TXNIP/NLRP3 axis. Life Sci 2025; 370:123561. [PMID: 40127859 DOI: 10.1016/j.lfs.2025.123561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/26/2025]
Abstract
AIM Obstetric antiphospholipid syndrome (OAPS) is a pregnancy-related complication characterized by trophoblast pyroptosis and placental injury induced by antiphospholipid antibodies (aPLs). M2-polarized macrophage-derived exosomes (M2-exos) exert anti-inflammatory, immunomodulatory, and growth-promoting effects in various autoimmune diseases and tumors. However, their role in OAPS is not yet clear. Therefore, in this study, we isolated M2-exos from M2 macrophages and investigated their effects on trophoblast proliferation, death, migration, invasion, and pyroptosis following stimulation using aPLs. MAIN METHODS First, we established an animal model of OAPS and thereafter treated the OAPS mice with exogenous M2-exos via injection through the tail vein. Then to clarify the roles of miR-20a-5p and thioredoxin-interacting protein (TXNIP) in OAPS, we performed gain- or loss-of-function assays, and used GraphPad Prism software to analyze the collected data with statistical significance set at P < 0.05. KEY FINDINGS MicroRNAs (miRNAs) sequencing revealed the enrichment of miR-20a-5p in M2-exos, and these M2-exos significantly alleviated aPLs-induced trophoblast dysfunction. Our results also indicated that M2-exos delivered miR-20a-5p to trophoblast cells directly targeted thioredoxin-interacting protein (TXNIP), and thus suppressed the TXNIP/NLRP3 pathway, reduced pyroptosis and inflammation in trophoblast cells, and improved placental function and fetal development. SIGNIFICANCE M2-exos improve pregnancy outcomes in OAPS via the miR-20a-5p/TXNIP/NLRP3 axis, and thus represent as a novel therapeutic approach for aPLs-induced OAPS.
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Affiliation(s)
- Hongyuan Zhang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China; Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China; The Laboratory of Medical Science and Technology Innovation Center (Institute of Translational Medicine), Shandong First Medical University (Shandong Academy of Medical Sciences) of China, Jinan 250117, Shandong, China
| | - Ning Jiang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Mingyang Xu
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China; Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Die Jing
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Tingting Dong
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China; Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Qian Liu
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China; Department of Obstetrics and Gynecology, Feixian County People's Hospital, Linyi 273400, Shandong, China
| | - Qingfeng Lv
- The Affiliated Taian City Central Hospital of Qingdao University, Taian 271000, Shandong, China
| | - Ruiheng Huo
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Pengzheng Chen
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China.
| | - Lei Li
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China; Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China; The Laboratory of Medical Science and Technology Innovation Center (Institute of Translational Medicine), Shandong First Medical University (Shandong Academy of Medical Sciences) of China, Jinan 250117, Shandong, China.
| | - Xietong Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China; Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China; The Laboratory of Medical Science and Technology Innovation Center (Institute of Translational Medicine), Shandong First Medical University (Shandong Academy of Medical Sciences) of China, Jinan 250117, Shandong, China.
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Ruan J, Xia Y, Ma Y, Xu X, Luo S, Yi J, Wu B, Chen R, Wang H, Yu H, Yang Q, Wu W, Sun D, Zhong J. Milk-derived exosomes as functional nanocarriers in wound healing: Mechanisms, applications, and future directions. Mater Today Bio 2025; 32:101715. [PMID: 40242483 PMCID: PMC12003018 DOI: 10.1016/j.mtbio.2025.101715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/22/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Wound healing presents a significant challenge in healthcare, imposing substantial physiological and economic burdens. While traditional treatments and stem cell therapies have shown benefits, milk-derived exosomes (MDEs) offer distinct advantages as a cell-free therapeutic approach. MDEs, isolated from mammalian milk, are characterized by their biocompatibility, ease of acquisition, and high yield, making them a promising tool for enhancing wound repair. This review provides a comprehensive analysis of the composition, sources, and extraction methods of MDEs, with a focus on their therapeutic role in both acute and diabetic chronic wounds. MDEs facilitate wound healing through the delivery of bioactive molecules, modulating key processes such as inflammation, angiogenesis, and collagen synthesis. Their ability to regulate complex wound-healing pathways underscores their potential for widespread clinical application. This review highlights the importance of MDEs in advancing wound management and proposes strategies to optimize their use in regenerative medicine.
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Affiliation(s)
- Jing Ruan
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Yuping Xia
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
| | - Yilei Ma
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Xiyao Xu
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
| | - Shihao Luo
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
| | - Jia Yi
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Baihui Wu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Rongbing Chen
- Department of Biomedical Engineering, City University of Hong Kong, 999077, Hong Kong Special Administrative Region of China
| | - Hanbing Wang
- Department of Biotechnology, The University of Hong Kong, 999077, Hong Kong Special Administrative Region of China
| | - Honggang Yu
- Hand and Foot Surgery, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu 322000, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
| | - Wei Wu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing 400044, China
- Jin Feng Laboratory, Chongqing, 401329, China
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Junbo Zhong
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
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Safaei M, Rajabi SS, Tirgar M, Namdar N, Dalfardi M, Mohammadifar F, Goodarzi A, Farmani AR, Ramezani V, Abpeikar Z. Exosome-based approaches in cancer along with unlocking new insights into regeneration of cancer-prone tissues. Regen Ther 2025; 29:202-216. [PMID: 40225049 PMCID: PMC11992408 DOI: 10.1016/j.reth.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/01/2025] [Accepted: 03/18/2025] [Indexed: 04/15/2025] Open
Abstract
Most eukaryotic cells secrete extracellular vesicles called exosomes, which are involved in intercellular communication. Exosomes play a role in tumor development and metastasis by transporting bioactive chemicals from cancerous cells to other cells in local and distant microenvironments. However, the potential of exosomes can be used by engineering them and considering different therapeutic approaches to overcome tumors. Exosomes are a promising drug delivery approach that can help decrease side effects from traditional treatments like radiation and chemotherapy by acting as targeted agents at the tumor site. The present review provides an overview of exosomes and various aspects of the role of exosomes in cancer development, which include these items: exosomes in cancer diagnosis, exosomes and drug delivery, exosomes and drug resistance, exosomal microRNAs and exosomes in tumor microenvironment, etc. Cancer stem cells release exosomes that nurture tumors, promoting unwanted growth and regeneration, and these types of exosomes should be inhibited. Ironically, exosomes from other cells, such as hepatocytes or mesenchymal stem cells (MSCs), are vital for healing organs like the liver and repairing gastric ulcers. Without proper treatment, this healing process can backfire, potentially leading to disease progression or even cancer. What can be found from various studies about the role of exosomes in the field of cancer is that exosomes act like a double-edged sword; on the other hand, natural exosomes in the body may play an important role in the process and progression of cancer, but by engineering exosomes, they can be directed towards target therapy and targeted delivery of drugs to tumor cells. By examining the role and application of exosomes in various mechanisms of cancer, it is possible to help treat this disease more efficiently and quickly in preclinical and clinical research.
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Affiliation(s)
- Mohsen Safaei
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Seyedeh Somayeh Rajabi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Mahtab Tirgar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Najmeh Namdar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Mahsa Dalfardi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farnia Mohammadifar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Arash Goodarzi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Ahmad Reza Farmani
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Vahid Ramezani
- Department of Pharmaceutics, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zahra Abpeikar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
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Saylor LM, Cherukuri R, Kammala AK, Richardson L, Ferrer M, Antich C, Frebert S, Han A, Menon R. Exosomal Delivery of Interleukin-10 Reduces Infection-Associated Inflammation in a 3D-Printed Model of a Humanized Feto-Maternal Interface. FASEB J 2025; 39:e70634. [PMID: 40356417 DOI: 10.1096/fj.202500545r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/05/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025]
Abstract
Spontaneous preterm birth (PTB) is associated with fetal inflammatory responses that are due to infections. Effective interventions to minimize these fetal responses are limited as drugs do not usually cross the feto-maternal interface (FMi) barrier, and reliable models to test drug efficacy and other pharmacologic parameters have not been available. We leveraged New Approach Methods (NAMs), including employing extracellular vesicles (exosomes of 30-200 nm) to deliver the anti-inflammatory cytokine interleukin (IL)-10 and using a high-throughput 3D-printed FMi model to test the efficacy of this delivery. IL-10 encapsulated exosomes were prepared by encapsulating recombinant IL-10 (rIL-10) using electroporation (eIL-10) or by transfecting RAW264.7 cells with an IL-10-expression plasmid (tIL-10) that enabled the expression of IL-10 in the cells during exosome biogenesis, which was then collected. Using a biocompatible polymer resin, we 3D printed a two-chambered FMi scaffold to mimic the amnion-decidual (feto-maternal) interface. Microchannels were integrated into the lower portions of the scaffold to facilitate intercellular communication. The device was composed of a mix of cells and gelatin methacrylate hydrogel material (lower part) and cell-specific culture medium (upper part). We showed that empty exosomes and IL-10-loaded exosomes delivered to the maternal side of the scaffold were able to cross to the fetal side of our FMi device. Furthermore, the effectiveness of eIL-10 and tIL-100 (500 ng) in reducing LPS-induced FMi inflammation on both the maternal and fetal sides was demonstrated by measuring pro-inflammatory IL-6 and IL-8 concentrations via multiplex assays at 6 h and 24 h timepoints. We determined that our 3D-printed two-chamber FMi model enabled the propagation of IL-10 encapsulated exosomes between the interconnected chambers. LPS treatment to the maternal decidua induced expression of pro-inflammatory IL-6 (p < 0.001) and IL-8 (p < 0.001) in both decidua and amnion compared with healthy (control) conditions. Co-treatment of LPS along with IL-10-loaded exosomes, regardless of its formulation, significantly reduced levels of the maternal and fetal inflammatory cytokines IL-6 and IL-8 at both 6 and 24 h after delivery. A high-throughput 3D-printed FMi model was used to show that IL-10 encapsulated exosomes can reduce infection-induced FMi inflammation. We describe two NAMs with the potential to significantly improve perinatal medicine: (1) an exosomal drug delivery method that protects the drug and can cross feto-maternal barriers and (2) a 3D-printed device that can be used for high-throughput drug screening.
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Affiliation(s)
- Leah M Saylor
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Rahul Cherukuri
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, Texas, USA
| | - Ananth K Kammala
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Lauren Richardson
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Marc Ferrer
- 3D Tissue Bioprinting Laboratory, National Center for Advancing Translational Sciences, National Institute of Sciences, Bethesda, Maryland, USA
| | - Cristina Antich
- 3D Tissue Bioprinting Laboratory, National Center for Advancing Translational Sciences, National Institute of Sciences, Bethesda, Maryland, USA
| | - Shayne Frebert
- 3D Tissue Bioprinting Laboratory, National Center for Advancing Translational Sciences, National Institute of Sciences, Bethesda, Maryland, USA
| | - Arum Han
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, Texas, USA
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas, USA
- Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA
| | - Ramkumar Menon
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
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Lin Y, Chen M, Yu Y, Xu P, Chen F, Zhou S, Xu J, Wu W, Zhu S, An Y, Zhang H, Wang W. Facile preparation of isolation columns filled with integral hybrid materials for efficient isolation of extracellular vesicles from microliter sample. Anal Chim Acta 2025; 1352:343939. [PMID: 40210292 DOI: 10.1016/j.aca.2025.343939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/11/2025] [Accepted: 03/13/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND Extracellular vesicles (EVs) and their anomalously altered cargoes represent a promising avenue for clinical diagnostics and prognostics. A critical challenge in EV research is the efficient isolation of these vesicles from complex biological samples with high recovery and purity. Although various of materials have good performance in EV isolation, these materials focus on the nanomaterials, which require multiple solution transfer steps in their use process. It will inevitably lead to sample loss, and is difficult to combine with online sample processing methods. RESULTS In this study, we introduce a novel isolation column for isolation of EVs, termed EvBHM, which leverages a bi-functional hybrid monolith and a polyethylene (PE) sieve plate. This design integrates the membrane insertion of distearoyl phospholipid ethanolamine (DSPE) with metal affinity chromatography (MAC), utilizing the interaction between titanium ions and the phospholipid membrane of EVs. The PE sieve plate serves as a robust support for the pore structure. This method provides a straightforward and user-friendly approach to prepare the isolation column, which demonstrates superior enrichment efficiency for EVs from microliter of cell culture media or plasma, ensuring minimal sample loss and high purity. Consequently, 37 up-regulated and 91 down-regulated proteins of plasma in colorectal cancer (CRC) patients are found over the health donors, and serval of them are associated with the occurrence and development of CRC. SIGNIFICANCE This method provides a straightforward and user-friendly approach to prepare of the isolation column, which demonstrates superior enrichment efficiency for EVs from microliter of cell culture media or serum as low as 10 μL, ensuring minimal sample loss and high purity. The results suggest this isolated method based on EvBHM isolation column is a promising strategy to search biomarkers for early diagnosis of cancers.
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Affiliation(s)
- Yujie Lin
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Mengxi Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Yuanyuan Yu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Pengfei Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Fengyu Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Shenyue Zhou
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Jiayu Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Wen Wu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Song Zhu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Yuxin An
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, 310051, China; NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Hangzhou, 310051, China.
| | - Haiyang Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
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Liu X, Ding L, Zhang A, Feng F, Zhou F, Wu Y. Dynamic characteristics of metabolism and small extracellular vesicles during malignant transformation of BEAS-2B cells induced by coal tar pitch extract. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 373:126108. [PMID: 40154873 DOI: 10.1016/j.envpol.2025.126108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 03/17/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
Lung cancer poses a significant global burden with rising morbidity and mortality. Coal tar pitch-induced lung cancer is an occupational disease where early detection is crucial but challenging due to unclear pathogenesis. We established a malignant transformation model using BEAS-2B cells treated with coal tar pitch extract (CTPE). Macro- and micro-observations showed CTPE-induced alterations, including changes in cell morphology, enhanced proliferation and migration abilities, upregulated EGFR expression, modified levels of CYP1A1 and GSTM1 metabolizing enzymes, and a transition towards a mesenchymal phenotype. These findings strongly suggest that the cells have undergone malignant transformation. Metabolomics analysis revealed changes in 1120 metabolites, with 31 co-expressed, mainly in energy and amino acid metabolism. Small extracellular vesicles (SEVs) concentrations and EGFR levels were significantly altered. Correlation analysis identified a relationship between these biomarkers, implying their potential significance as early events in the initiation and progression of lung cancer. These findings provide valuable insights and a rationale for lung cancer screening and mechanistic investigations, thereby contributing to a deeper understanding of the disease.
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Affiliation(s)
- Xia Liu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Lihua Ding
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Aiai Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Feifei Feng
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Fang Zhou
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
| | - Yongjun Wu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
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Han Y, Guo XP, Zhi QM, Xu JJ, Liu F, Kuang YT. Circulating exosomal miR-17-92 cluster serves as a novel noninvasive diagnostic marker for patients with gastric cancer. World J Gastrointest Oncol 2025; 17:104776. [DOI: 10.4251/wjgo.v17.i5.104776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/25/2025] [Accepted: 03/13/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is among the most common malignant tumors and remains a leading cause of cancer-related mortality worldwide. Furthermore, exosomal miRNAs are regarded as promising noninvasive biomarkers for diagnosing malignant tumors.
AIM To investigate the expression of exosomal miR-17-92 clusters and develop a potential biomarker for GC diagnosis
METHODS Exosomes were isolated from serum samples obtained from 72 GC patients and 20 healthy controls. The isolated exosomes were validated using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Exosomal RNA was then extracted, and the expression profile of the miR-17-92 cluster was analyzed using qRT-PCR. Statistical methods were employed to evaluate the relationship between the serum exosomal miR-17-92 cluster expression and the clinicopathological parameters of GC patients as well as to assess the diagnostic utility of these miRNAs.
RESULTS The expression of four members of the exosomal miR-17-92 cluster-miR-17, miR-18, miR-19a, and miR-92-was significantly upregulated in the serum samples of patients with GC compared with those of healthy controls. The miR-17-92 cluster panel demonstrated substantially higher clinical diagnostic value for GC than any individual component or pair. Additionally, the expression of traditional tumor biomarkers-carcinoembryonic antigen and carbohydrate antigen 19-9-was significantly elevated in the serum of patients with GC compared with that of healthy controls. Each biomarker, whether alone or in combination, effectively differentiated the patients from healthy controls. Furthermore, a combined panel of the two traditional tumor biomarkers and the four miR-17-92 cluster members exhibited the highest diagnostic accuracy for GC. Elevated miR-17-92 expression was also strongly associated with tumor size, tumor depth, lymph node metastasis, distant metastasis, and tumor-node-metastasis stage.
CONCLUSION Our findings revealed that the circulating exosomal miR-17-92 cluster may be used as a potential noninvasive biomarker to improve diagnostic efficiency for GC.
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Affiliation(s)
- Ye Han
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Xing-Po Guo
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Qiao-Ming Zhi
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Jing-Jing Xu
- Department of Central Laboratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Fei Liu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Yu-Ting Kuang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
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Jain S, Murmu A, Chauhan A. Advancing Alzheimer's disease therapy through engineered exosomal Macromolecules. Brain Res 2025; 1855:149590. [PMID: 40120708 DOI: 10.1016/j.brainres.2025.149590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/03/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Exosomes are a subject of continuous investigation due to their function as extracellular vesicles (EVs) that significantly contribute to the pathophysiology of certain neurodegenerative disorders (NDD), including Alzheimer's disease (AD). Exosomes have shown the potential to carry both therapeutic and pathogenic materials; hence, researchers have used exosomes for medication delivery applications. Exosomes have reduced immunogenicity when used as natural drug delivery vehicles. This guarantees the efficient delivery of the medication without causing significant side reactions. Exosomes have lately enabled the potential for drug delivery in AD, along with promising future therapeutic uses for the detection of neurodegenerative disorders. Furthermore, exosomes have been examined for their prospective use in illness diagnosis and prediction before the manifestation of symptoms. This review will document prior studies and will concentrate on the rationale behind the substantial potential of exosomes in the treatment of AD and their prospective use as a diagnostic and predictive tool for this condition.
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Affiliation(s)
- Smita Jain
- Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Kishangarh, Rajasthan, India.
| | - Ankita Murmu
- Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Kishangarh, Rajasthan, India
| | - Aparna Chauhan
- Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Kishangarh, Rajasthan, India
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Li LS, Chen XH, Pei Y, Xie XL, Wu CT, Cai S, Li J, Gong W. A label-free fluorescence aptasensor for salivary exosomes based on a nano-micro dual-scale signal amplification strategy. Talanta 2025; 287:127638. [PMID: 39893729 DOI: 10.1016/j.talanta.2025.127638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/28/2024] [Accepted: 01/23/2025] [Indexed: 02/04/2025]
Abstract
Oral squamous cell carcinoma (OSCC) is the most prevalent histological subtype of oral cancer and urgently requires a noninvasive approach for timely detection to improve patients' prognose. Salivary exosome act as a promising biomarker, while the complex and expensive analytical methods impeded its popularization in clinical applications. In this study, we developed a label-free aptasensor for salivary exosomes that utilizes a "one exosome to multiple carbon dots" signal conversion method along with nano-micro dual-scale signal amplification strategy. SiO2 microspheres served as substrates, while carbon dots acted as luminophores, with CD63 aptamers functioning as selective recognition elements. Exosomes compete to bind with the aptamers, thereby leading to the release of non-specifically adsorbed carbon dots from the substrates. The concentration of exosomes is proportional to the variation in fluorescence intensity, enabling highly sensitive detection in artificial saliva samples, with a favorable linearity range of 2.5 × 102∼5 × 108 particles/mL and a relatively low LOD of 100 particles/mL. The anti-interference ability is deemed acceptable, and the fabrication process is affordable coupled with a straightforward signal output mode. The aptasensor was applied successfully to distinguish OSCC patients from healthy individuals, suggesting its potential for screening OSCC in physical examination centers and communities.
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Affiliation(s)
- Lu-Shuang Li
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou, 570228, China
| | - Xiao-Hao Chen
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou, 570228, China
| | - Yu Pei
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China
| | - Xiao-Lin Xie
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China
| | - Cong-Ting Wu
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China
| | - Shuang Cai
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China
| | - Jing Li
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China; Institute of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China.
| | - Wei Gong
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China; Institute of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China.
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50
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Yu Q, Ye S, Chen M, Sun P, Weng N. A novel function for exosomes in depression. Life Sci 2025; 369:123558. [PMID: 40089099 DOI: 10.1016/j.lfs.2025.123558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/01/2025] [Accepted: 03/08/2025] [Indexed: 03/17/2025]
Abstract
Exosomes are a class of extracellular vesicles that encompass a diverse array of bioactive molecules, including proteins, lipids, mRNA, and microRNA(miRNA). Virtually all cell types release exosomes under both physiological and pathological conditions. In addition to electrical and chemical signals, exosomes are an alternative route of signaling between cells in the brain. In the brain, they are involved in processes such as synaptic plasticity, neuronal stress response, intercellular communication, and neurogenesis. A number of studies have shown that exosomes regulate the occurrence and development of depression by participating in the regulation of hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, immune inflammatory response and other mechanisms, showing that they may become potential biological agents for the diagnosis and treatment of depression. In addition, exosomes have the ability to easily cross the blood-brain barrier, making them ideal drug or molecular delivery tools for the central nervous system. Engineered exosomes have good brain targeting ability, and their research in central nervous system diseases has begun to emerge. However, the molecular pathways involved in the pathogenesis of depression remain unknown, and further studies are needed to fully understand the role of exosomes in the development or improvement of depression. Therefore, in this review, we mainly focus on the diagnostic performance and therapeutic effect of exosomes in depression, and explore the advantages of exosomes as biomarkers and gene delivery vectors for depression.
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Affiliation(s)
- Qingying Yu
- School of Pharmacy, Shandong University of Chinese Medicine, Jinan 250000, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - Shuyi Ye
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - Mengxue Chen
- Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, China
| | - Peng Sun
- Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250000, China.
| | - Ning Weng
- Department of Chinese Medicine, Shandong Mental Health Center, Shandong University, Jinan, China.
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