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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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Zhang L. MicroRNA-214-3p Delivered by Bone Marrow Mesenchymal Stem Cells-Secreted Exosomes Affects Oxidative Stress in Alzheimer's Disease Rats by Targeting CD151. Organogenesis 2025; 21:2489673. [PMID: 40287960 PMCID: PMC12036478 DOI: 10.1080/15476278.2025.2489673] [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: 08/20/2024] [Revised: 02/24/2025] [Accepted: 04/02/2025] [Indexed: 04/29/2025] Open
Abstract
OBJECTIVE This study probed the effect of targeted regulation of CD151 by microRNA-214-3p (miR-214-3p) delivered by bone marrow mesenchymal stem cells-secreted exosomes (BMSCs-exo) on oxidative stress and apoptosis of neurons in Alzheimer's disease (AD). METHODS Rat BMSCs were isolated, from which MSCs-exo were extracted and identified. The AD rat model was established and injected with MSC-exo suspension. Meanwhile, miR-214-3p and CD151 interfering lentivirus were transfected in MSCs. After injection, learning and cognitive ability of the rats were assessed, as well as neuronal apoptosis and oxidative stress injury. miR-214-3p and CD151 levels were determined, and their relationship was explored. RESULTS AD rats had prolonged escape latency, weakened learning and cognitive ability, increased neuronal apoptosis in the hippocampal CA3 region, and aggravated oxidative stress. After MSC-exo injection, these changes in AD rats were partially rescued. CD151 was targeted by miR-214-3p, and MSC-exo improved AD in rats through the miR-214-3p/CD151 axis. CONCLUSION MSC-exo down-regulates CD151 by targeting miR-214-3p to enhance antioxidant capacity, thereby improving the pathological injury of AD rats.
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Affiliation(s)
- Luzy Zhang
- School of Pharmacy and Food Science, Zhuhai College of Science and Technology (Zhuhai College of Jilin University), Zhuhai, Guangdong, 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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Sun S, Rong J, Wang C, Li R, Zhang H, Wang W, Duan H, Nie Z, Xiang D, Liu Z. Intranasal administration of exosomes derived from adipose mesenchymal stem cells ameliorates depressive-like behaviors and inhibits inflammation via AMPK/mTOR-mediated autophagy. J Affect Disord 2025; 382:227-247. [PMID: 40250814 DOI: 10.1016/j.jad.2025.04.059] [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: 08/15/2024] [Revised: 02/25/2025] [Accepted: 04/10/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND Major depressive disorder (MDD) is a severe, and often treatment-resistant, psychiatric disorder. Mesenchymal stem cell-derived exosomes have been shown to be neuroprotective. Here we employed adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) as a novel therapeutic approach for depressive-like behavior in mice and explored the underlying mechanisms. METHODS ADSC-Exos were administered intranasally to mice subjected to chronic restraint stress to assess behavioral changes and neuroprotection in terms of apoptosis, AMPK-mTOR signaling, and NLRP3 pathway activation by western blotting, microglial activation by immunofluorescence, and changes in serum inflammatory factors by ELISA. The effects of ADSC-Exos were also studied in vitro in HT22 cells. RESULTS ADSC-Exos significantly improved depressive-like behavior, anxiety-like behavior, and cognitive function in mice. ADSC-Exos had significant neuroprotective effects, including reducing neuronal apoptosis and promoting autophagy by activating AMPK-mTOR signaling, ultimately reducing neuroinflammation. In vitro, ADSC-Exos inhibited corticosterone-induced apoptosis, activated autophagy in an AMPK pathway-dependent manner, and inhibited NLRP3 inflammasome activation. CONCLUSION ADSC-Exos may be a potential treatment for MDD by alleviating depressive-like behaviors and protecting against tissue injury, possibly through activation of AMPK-mTOR signaling and inhibition of NLRP3 inflammasome-mediated neuroinflammation.
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Affiliation(s)
- Siqi Sun
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Jingtong Rong
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Chao Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Ruiling Li
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Honghan Zhang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Wei Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Hao Duan
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Zhaowen Nie
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Dan Xiang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China.
| | - Zhongchun Liu
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, PR China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, PR China.
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Pineiro-Alonso L, Rubio-Prego I, Lobyntseva A, González-Freire E, Langer R, Alonso MJ. Nanomedicine for targeting brain Neurodegeneration: Critical barriers and circadian rhythm Considerations. Adv Drug Deliv Rev 2025; 222:115606. [PMID: 40383234 DOI: 10.1016/j.addr.2025.115606] [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: 11/29/2024] [Revised: 04/07/2025] [Accepted: 05/10/2025] [Indexed: 05/20/2025]
Abstract
The development of novel therapies for central nervous system (CNS) diseases, particularly neurodegenerative disorders like Alzheimer's disease (AD), is a critical global health priority. Biotherapeutics, such as monoclonal antibodies (mAbs) and RNA-based therapies, have shown potential for treating brain disorders. However, their clinical progress is limited by their difficult access to their brain targets. At the preclinical level, nanotechnology has been shown, to help these molecules overcome the biological barriers that imped their adequate brain delivery. This review highlights advances in this area and the challenges for the translation to the clinic. Key nanotechnology-based strategies, such as surface modifications utilizing endogenous protein corona, functionalization with targeting ligands, therapeutic ultrasound-mediated microbubble oscillation were particularly analyzed. Additionally, in line with the focus of the Special Issue, this review integrates the concept of chronotherapy, with a focus on AD treatment, highlighting the idea that, by aligning nanoparticle (NP)-based drug delivery with circadian rhythms, it may be possible to improve therapeutic outcomes. Finally, the article analyzes current strategies in CNS drug delivery in clinical trials and provides future directions within this frame, notably in the area of AD.
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Affiliation(s)
- Laura Pineiro-Alonso
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacology, Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782, Spain
| | - Inés Rubio-Prego
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacology, Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782, Spain
| | - Alexandra Lobyntseva
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacology, Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782, Spain
| | - Eva González-Freire
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacology, Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782, Spain
| | - Robert Langer
- Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - María José Alonso
- Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacology, Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782, Spain.
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Abdi SMY, Al-Bakri SSM, Nordin N. Insights on the Characteristics and Therapeutic Potential of Mesenchymal Stem Cell-derived Exosomes for Mitigation of Alzheimer's Disease's Pathogenicity: A Systematic Review. Cell Biochem Biophys 2025; 83:1399-1414. [PMID: 39436580 DOI: 10.1007/s12013-024-01598-x] [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] [Accepted: 04/22/2024] [Indexed: 10/23/2024]
Abstract
Alzheimer's disease (AD) remains a progressive neurodegenerative disease with no cure. Treatment of AD relies on administering drugs that only subside the symptoms. In recent studies, mesenchymal stem cell (MSC)-exosomes have been marked to possess therapeutic potential for treating AD. This study aims to systematically review and analyse findings that focus on the isolation, characterisation, and sources of MSC-derived exosomes used to unravel the therapeutic potential of these exosomes targeting AD using in vitro and in vivo models. It is hypothesised that MSC-exosomes exhibit high therapeutic potential for AD treatment by exerting various modes of action. PubMed, Scopus, and Medline were used to find relevant published works from January 2016 until December 2020, using assigned keywords including "Alzheimer's disease", "secretome", and "exosomes". Only research articles meeting the predefined inclusion/exclusion criteria were selected and analysed. The risk of bias was assessed using the Office of Health Assessment and Translation tool (OHAT). A total of 17 eligible in vivo and in vitro studies were included in this review. Bone marrow-derived stem cells (BMSCs) were the most used source for exosome isolation, even though studies on exosomes from adipose-derived stem cells (ADSCs) and human umbilical cord stem cells (HUCSCs) provide more information on the characteristics. When the risk of bias was assessed, the studies presented various levels of biases. Notably, the in vitro and in vivo studies revealed neuroprotective properties of MSC-exosomes through different modes of action to alleviate AD pathology. Our review discovered that most MSC exosomes could degrade Aβ plaques, enhance neurogenesis, extenuate neuroinflammatory response through microglial activation, regulate apoptosis and reduce oxidative stress. Delivery of exosomal micro-RNAs was also found to reduce neuroinflammation. Findings from this review provided convincing systematic evidence highlighting the therapeutic properties of MSC-derived exosomes as a prospective source for cell-free (acellular) therapy in treating AD.
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Affiliation(s)
- Sarah Mohammed Yousuf Abdi
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Siti Sarah Mustaffa Al-Bakri
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Norshariza Nordin
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
- Malaysian Research Institute on Ageing (MyAgeing™), Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
- Genetics & Regenerative Medicine (ReGEN) Research Group, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
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Yao T, Dong X, Wang X, Liu X, Fu L, Li L. Engineering exosomes for mRNA delivery: a review. Int J Biol Macromol 2025; 316:144662. [PMID: 40425113 DOI: 10.1016/j.ijbiomac.2025.144662] [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: 03/28/2025] [Revised: 05/22/2025] [Accepted: 05/24/2025] [Indexed: 05/29/2025]
Abstract
Messenger RNA (mRNA) has emerged as a highly promising therapeutic approach with successful applications across various diseases. Developing safe and efficient carriers to preserve mRNA integrity during in vivo delivery is critical for ensuring the therapeutic efficacy of mRNA-based treatments. Exosomes, natural nanovesicles secreted by cells, possess several favorable properties, including excellent biocompatibility, low immunogenicity, the unique ability to traverse physiological barriers and to target specific cell types, which make them attractive candidates for mRNA delivery. Moreover, exosomes can be engineered to increase their yield, enhance targeting specificity, improve cellular uptake efficiency, and extend their circulation time in the bloodstream. However, several challenges must be addressed urgently, including exosome heterogeneity, scalable production methods, and the efficient encapsulation of mRNA cargo. This review highlights the advantages and limitations of exosome-based mRNA delivery systems, discusses current strategies for engineering exosomes to improve mRNA delivery, and describes their applications in disease treatment-emphasizing their potential to advance precision medicine and targeted therapies.
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Affiliation(s)
- Ting Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine,79 Qingchun Rd., Hangzhou City 310003, China
| | - Xiangmin Dong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine,79 Qingchun Rd., Hangzhou City 310003, China
| | - Xinyu Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine,79 Qingchun Rd., Hangzhou City 310003, China
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine,79 Qingchun Rd., Hangzhou City 310003, China
| | - Liyun Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine,79 Qingchun Rd., Hangzhou City 310003, China; Department of Hepatology, Ningbo No.2 Hospital, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine,79 Qingchun Rd., Hangzhou City 310003, 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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Varshney V, Gabble BC, Bishoyi AK, Varma P, Qahtan SA, Kashyap A, Panigrahi R, Nathiya D, Chauhan AS. Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases. Mol Neurobiol 2025:10.1007/s12035-025-05026-w. [PMID: 40347374 DOI: 10.1007/s12035-025-05026-w] [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: 03/20/2025] [Accepted: 05/02/2025] [Indexed: 05/12/2025]
Abstract
Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.
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Affiliation(s)
- Vibhav Varshney
- Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Baneen C Gabble
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq.
- Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq.
| | - Ashok Kumar Bishoyi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, India
| | - Pooja Varma
- Department of Psychology, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Sarraa Ahmad Qahtan
- Department of Anesthesia Techniques, Health and Medical Techniques College, Alnoor University, Mosul, Iraq
| | - Aditya Kashyap
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Rajashree Panigrahi
- Department of Microbiology, IMS and SUM Hospital, Siksha O Anusandhan Deemed to Be University, Bhubaneswar, Odisha, 751003, India
| | - Deepak Nathiya
- Department of Pharmacy Practice, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - Ashish Singh Chauhan
- Division of Research and Innovation, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, India
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Mehdizadeh S, Mamaghani M, Hassanikia S, Pilehvar Y, Ertas YN. Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies. J Nanobiotechnology 2025; 23:329. [PMID: 40319325 PMCID: PMC12049023 DOI: 10.1186/s12951-025-03352-8] [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: 11/04/2024] [Accepted: 03/24/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods. MAIN BODY This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions. CONCLUSION By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.
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Affiliation(s)
- Sepehr Mehdizadeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mobin Mamaghani
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Younes Pilehvar
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, 38039, Türkiye.
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Hoang VT, Nguyen QT, Phan TTK, Pham TH, Dinh NTH, Anh LPH, Dao LTM, Bui VD, Dao H, Le DS, Ngo ATL, Le Q, Nguyen Thanh L. Tissue Engineering and Regenerative Medicine: Perspectives and Challenges. MedComm (Beijing) 2025; 6:e70192. [PMID: 40290901 PMCID: PMC12022429 DOI: 10.1002/mco2.70192] [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: 07/06/2024] [Revised: 12/30/2024] [Accepted: 03/04/2025] [Indexed: 04/30/2025] Open
Abstract
From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quyen Thi Nguyen
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang Thi Kieu Phan
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang H. Pham
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Nhung Thi Hong Dinh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Le Phuong Hoang Anh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Lan Thi Mai Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Van Dat Bui
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- School of Chemical EngineeringCollege of EngineeringSungkyunkwan University (SKKU)SuwonRepublic of Korea
| | - Hong‐Nhung Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Duc Son Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Anh Thi Lan Ngo
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quang‐Duong Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
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12
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Bashirrohelleh MA, Bavarsad K, Khodadadi A, Shohan M, Asadirad A. Curcumin-enhanced stem cell exosomes: A novel approach to modulating neuroinflammation and improving cognitive function in a rat model of Alzheimer's disease. Eur J Pharmacol 2025; 999:177695. [PMID: 40315951 DOI: 10.1016/j.ejphar.2025.177695] [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: 11/25/2024] [Revised: 04/22/2025] [Accepted: 04/30/2025] [Indexed: 05/04/2025]
Abstract
The effect of Curcumin-enhanced stem cell exosomes on the learning and memory impairment induced by streptozotocin (STZ) and neuro-inflammation in rats was evaluated. An animal model of Alzheimer's disease (AD) was established by intracerebroventricular (ICV) injection of STZ (3 mg/kg) in male Wistar rats (250 ± 50 g). ICV STZ injections chronically reduce cerebral glucose uptake and produce other effects similar to pathological, molecular and behavioral features of AD. Numerous studies confirmed the anti-inflammatory and antioxidant properties of curcumin (a natural polyphenol) against free radicals, as well as its ability to inhibit the aggregation of proteins such as beta-amyloid and alpha-synuclein in disorders such as AD and Parkinson's disease. The use of extracellular vesicles has garnered a lot of interest in research studies because of the important roles that mesenchymal stem cell-derived exosomes play in permeability, retention, and drug delivery as well as their ability to reduce inflammatory cytokines (TNF-α, IL-1β, and IL-6). Furthermore, researches highlighted the positive effect of curcumin on neuronal differentiation of stem cells in vivo and in vitro. Since studies emphasized the ameliorating effect of curcumin-treated macrophage-exosomes on symptoms of Alzheimer's disease by inhibiting tau protein phosphorylation, we proposed that Curcumin-primed MSC exosomes may offer greater efficacy to alleviate AD compared to naïve MSC exosomes. In this study, we investigated the effect of curcumin in stimulating the anti-inflammatory potential of exosome-derived stem cells. We evaluated the effect of MSC-EXO and pre-treated MSC-EXO with curcumin (CUR-MSC-EXO) on inhibiting inflammation and memory and learning impairments. Following four intraperitoneal injections of MSC-EXO and CUR-MSC-EXO at a dosage of 30μg/body over 30 days, we found that MSC-EXO and CUR-MSC-EXO elevated anti-inflammatory cytokines (IL10, TGF-β) and reduced pro-inflammatory cytokines (IL1, TNF-α) in peripheral blood compared to the AD group. The elevated level of M2 anti-inflammatory microglia markers (Arg1, CD206) and decreased level expression of M1 pro-inflammatory markers (iNOS, CD86) indicated that the CUR-MSC-EXO effect was more significant in the polarization of microglia into the M2 phenotype in the rat hippocampus. Both treatment groups demonstrated improvements in memory and learning skills. The results of the passive avoidance learning in the rats with STZ-induced memory impairment, however, were better in the CUR-MSC-EXO. Additionally, after therapy, a decrease in degenerative neurons was seen. Therefore, using curcumin may stimulate the anti-inflammatory and neuroprotective potential of exosome-derived stem cells which could provide hope for Alzheimer's disease treatment in the future.
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Affiliation(s)
- Mohammad-Ali Bashirrohelleh
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kowsar Bavarsad
- Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Persian Gulf Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Khodadadi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Shohan
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran
| | - Ali Asadirad
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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13
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Ponce-Lopez T. Peripheral Inflammation and Insulin Resistance: Their Impact on Blood-Brain Barrier Integrity and Glia Activation in Alzheimer's Disease. Int J Mol Sci 2025; 26:4209. [PMID: 40362446 PMCID: PMC12072112 DOI: 10.3390/ijms26094209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.
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Affiliation(s)
- Teresa Ponce-Lopez
- Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico
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14
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Jung YH, Jo HY, Kim DH, Oh YJ, Kim M, Na S, Song HY, Lee HJ. Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease. Int J Nanomedicine 2025; 20:4903-4917. [PMID: 40259919 PMCID: PMC12011032 DOI: 10.2147/ijn.s513816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 04/07/2025] [Indexed: 04/23/2025] Open
Abstract
Alzheimer's disease (AD) and Parkinson's disease (PD) are representative neurodegenerative diseases with abnormal energy metabolism and altered distribution and deformation of mitochondria within neurons, particularly in brain regions such as the hippocampus and substantia nigra. Neurons have high energy demands; thus, maintaining a healthy mitochondrial population is important for their biological function. Recently, exosomes have been reported to have mitochondrial regulatory potential and antineurodegenerative properties. This review presents the mitochondrial abnormalities in brain cells associated with AD and PD and the potential of exosomes to treat these diseases. Specifically, it recapitulates research on the molecular mechanisms whereby exosomes regulate mitochondrial biogenesis, fusion/fission dynamics, mitochondrial transport, and mitophagy. Furthermore, this review discusses exosome-triggered signaling pathways that regulate nuclear factor (erythroid-derived 2)-like 2-dependent mitochondrial antioxidation and hypoxia inducible factor 1α-dependent metabolic reprogramming. In summary, this review aims to provide a profound understanding of the regulatory effect of exosomes on mitochondrial function in neurons and to propose exosome-mediated mitochondrial regulation as a promising strategy for AD and PD.
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Affiliation(s)
- Young Hyun Jung
- Department of Physiology, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hyo Youn Jo
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Dae Hyun Kim
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Yeon Ju Oh
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Minsoo Kim
- Department of Physiology, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Seunghyun Na
- Department of Physiology, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Ho-Yeon Song
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea
| | - Hyun Jik Lee
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of Korea
- Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, 28644, Republic of Korea
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15
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Williams A, Branscome H, Kashanchi F, Batrakova EV. Targeting of Extracellular Vesicle-Based Therapeutics to the Brain. Cells 2025; 14:548. [PMID: 40214500 PMCID: PMC11989082 DOI: 10.3390/cells14070548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 03/28/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025] Open
Abstract
Extracellular vesicles (EVs) have been explored as promising vehicles for drug delivery. One of the most valuable features of EVs is their ability to cross physiological barriers, particularly the blood-brain barrier (BBB). This significantly enhances the development of EV-based drug delivery systems for the treatment of CNS disorders. The present review focuses on the factors and techniques that contribute to the successful delivery of EV-based therapeutics to the brain. Here, we discuss the major methods of brain targeting which includes the utilization of different administration routes, capitalizing on the biological origins of EVs, and the modification of EVs through the addition of specific ligands on to the surface of EVs. Finally, we discuss the current challenges in large-scale EV production and drug loading while highlighting future perspectives regarding the application of EV-based therapeutics for brain delivery.
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Affiliation(s)
- Anastasia Williams
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 248, 10900 University Blvd, Manassas, VA 20110, USA; (A.W.); (H.B.); (F.K.)
| | - Heather Branscome
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 248, 10900 University Blvd, Manassas, VA 20110, USA; (A.W.); (H.B.); (F.K.)
- American Type Culture Collection (ATCC), Manassas, VA 20110, USA
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 248, 10900 University Blvd, Manassas, VA 20110, USA; (A.W.); (H.B.); (F.K.)
| | - Elena V. Batrakova
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 248, 10900 University Blvd, Manassas, VA 20110, USA; (A.W.); (H.B.); (F.K.)
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16
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Vahab SA, V VK, Kumar VS. Exosome-based drug delivery systems for enhanced neurological therapeutics. Drug Deliv Transl Res 2025; 15:1121-1138. [PMID: 39325272 DOI: 10.1007/s13346-024-01710-x] [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] [Accepted: 09/09/2024] [Indexed: 09/27/2024]
Abstract
Exosomes are small extracellular vesicles naturally secreted by cells into body fluids, enriched with bioactive molecules such as RNAs, proteins, and lipids. These nanosized vesicles play a crucial role in physiological and pathological processes by facilitating intercellular communication and modulating cellular responses, particularly within the central nervous system (CNS). Their ability to cross the blood-brain barrier and reflect the characteristics of their parent cells makes exosomal cargo a promising candidate for biomarkers in the early diagnosis and clinical assessment of neurological conditions. This review offers a comprehensive overview of current knowledge on the characterization of mammalian-derived exosomes, their application as drug delivery systems for neurological disorders, and ongoing clinical trials involving exosome-loaded cargo. Despite their promising attributes, a significant challenge remains the lack of standardized isolation methods, as current techniques are often complex, costly, and require sophisticated equipment, affecting the scalability and affordability of exosome-based therapies. The review highlights the engineering potential of exosomes, emphasizing their ability to be customized for targeted therapeutic delivery through surface modification or conjugation. Future advancements in addressing these challenges and leveraging the unique properties of exosomes could lead to innovative and effective therapeutic strategies in neurology.
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Affiliation(s)
- Safa A Vahab
- Amrita School of Pharmacy, Amrita Institute of Medical Sciences & Research Centre, Amrita Vishwa Vidyapeetham, Kochi-682041, Kerala, India
| | - Vyshma K V
- Amrita School of Pharmacy, Amrita Institute of Medical Sciences & Research Centre, Amrita Vishwa Vidyapeetham, Kochi-682041, Kerala, India
| | - Vrinda S Kumar
- Amrita School of Pharmacy, Amrita Institute of Medical Sciences & Research Centre, Amrita Vishwa Vidyapeetham, Kochi-682041, Kerala, India.
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17
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Li J, Wang Z, Wei Y, Li W, He M, Kang J, Xu J, Liu D. Advances in Tracing Techniques: Mapping the Trajectory of Mesenchymal Stem-Cell-Derived Extracellular Vesicles. CHEMICAL & BIOMEDICAL IMAGING 2025; 3:137-168. [PMID: 40151822 PMCID: PMC11938168 DOI: 10.1021/cbmi.4c00085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 03/29/2025]
Abstract
Mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) are nanoscale lipid bilayer vesicles secreted by mesenchymal stem cells. They inherit the parent cell's attributes, facilitating tissue repair and regeneration, promoting angiogenesis, and modulating the immune response, while offering advantages like reduced immunogenicity, straightforward administration, and enhanced stability for long-term storage. These characteristics elevate MSC-EVs as highly promising in cell-free therapy with notable clinical potential. It is critical to delve into their pharmacokinetics and thoroughly elucidate their intracellular and in vivo trajectories. A detailed summary and evaluation of existing tracing strategies are needed to establish standardized protocols. Here, we have summarized and anticipated the research progress of MSC-EVs in various biomedical imaging techniques, including fluorescence imaging, bioluminescence imaging, nuclear imaging (PET, SPECT), tomographic imaging (CT, MRI), and photoacoustic imaging. The challenges and prospects of MSC-EV tracing strategies, with particular emphasis on clinical translation, have been analyzed, with promising solutions proposed.
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Affiliation(s)
- Jingqi Li
- State
Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory
of Molecular Recognition and Biosensing, Frontiers Science Centers
for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Zhaoyu Wang
- State
Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory
of Molecular Recognition and Biosensing, Frontiers Science Centers
for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Yongchun Wei
- State
Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory
of Molecular Recognition and Biosensing, Frontiers Science Centers
for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Wenshuai Li
- State
Key Laboratory for Crop Stress Resistance and High-Efficiency Production,
Shaanxi Key Laboratory of Agricultural and Environmental Microbiology,
College of Life Sciences, Northwest A&F
University, Yangling, Shaanxi 712100, China
| | - Mingzhu He
- State
Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory
of Molecular Recognition and Biosensing, Frontiers Science Centers
for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Jingjing Kang
- State
Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory
of Molecular Recognition and Biosensing, Frontiers Science Centers
for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Jia Xu
- State
Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory
of Molecular Recognition and Biosensing, Frontiers Science Centers
for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Dingbin Liu
- State
Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory
of Molecular Recognition and Biosensing, Frontiers Science Centers
for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
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18
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Wang F, Feng J, Jin A, Shao Y, Shen M, Ma J, Lei L, Liu L. Extracellular Vesicles for Disease Treatment. Int J Nanomedicine 2025; 20:3303-3337. [PMID: 40125438 PMCID: PMC11928757 DOI: 10.2147/ijn.s506456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/20/2025] [Indexed: 03/25/2025] Open
Abstract
Traditional drug therapies suffer from problems such as easy drug degradation, side effects, and treatment resistance. Traditional disease diagnosis also suffers from high error rates and late diagnosis. Extracellular vesicles (EVs) are nanoscale spherical lipid bilayer vesicles secreted by cells that carry various biologically active components and are integral to intercellular communication. EVs can be found in different body fluids and may reflect the state of the parental cells, making them ideal noninvasive biomarkers for disease-specific diagnosis. The multifaceted characteristics of EVs render them optimal candidates for drug delivery vehicles, with evidence suggesting their efficacy in the treatment of various ailments. However, poor stability and easy degradation of natural EVs have affected their applications. To solve the problems of poor stability and easy degradation of natural EVs, they can be engineered and modified to obtain more stable and multifunctional EVs. In this study, we review the shortcomings of traditional drug delivery methods and describe how to modify EVs to form engineered EVs to improve their utilization. An innovative stimulus-responsive drug delivery system for EVs has also been proposed. We also summarize the current applications and research status of EVs in the diagnosis and treatment of different systemic diseases, and look forward to future research directions, providing research ideas for scholars.
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Affiliation(s)
- Fangyan Wang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
| | - Jiayin Feng
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
| | - Anqi Jin
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
| | - Yunyuan Shao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
| | - Mengen Shen
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
| | - Jiaqi Ma
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
| | - Lanjie Lei
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
| | - Liangle Liu
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325200, People’s Republic of China
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19
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Odehnalová N, Šandriková V, Hromadka R, Skaličková M, Dytrych P, Hoskovec D, Kejík Z, Hajduch J, Vellieux F, Vašáková MK, Martásek P, Jakubek M. The potential of exosomes in regenerative medicine and in the diagnosis and therapies of neurodegenerative diseases and cancer. Front Med (Lausanne) 2025; 12:1539714. [PMID: 40182844 PMCID: PMC11966052 DOI: 10.3389/fmed.2025.1539714] [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: 12/04/2024] [Accepted: 02/06/2025] [Indexed: 04/05/2025] Open
Abstract
Exosomes, nanosized extracellular vesicles released by various cell types, are intensively studied for the diagnosis and treatment of cancer and neurodegenerative diseases, and they also display high usability in regenerative medicine. Emphasizing their diagnostic potential, exosomes serve as carriers of disease-specific biomarkers, enabling non-invasive early detection and personalized medicine. The cargo loading of exosomes with therapeutic agents presents an innovative strategy for targeted drug delivery, minimizing off-target effects and optimizing therapeutic interventions. In regenerative medicine, exosomes play a crucial role in intercellular communication, facilitating tissue regeneration through the transmission of bioactive molecules. While acknowledging existing challenges in standardization and scalability, ongoing research efforts aim to refine methodologies and address regulatory considerations. In summary, this review underscores the transformative potential of exosomes in reshaping the landscape of medical interventions, with a particular emphasis on cancer, neurodegenerative diseases, and regenerative medicine.
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Affiliation(s)
- Nikola Odehnalová
- NEXARS Research and Development Center C2P s.r.o, Chlumec nad Cidlinou, Czechia
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
| | - Viera Šandriková
- NEXARS Research and Development Center C2P s.r.o, Chlumec nad Cidlinou, Czechia
| | - Róbert Hromadka
- NEXARS Research and Development Center C2P s.r.o, Chlumec nad Cidlinou, Czechia
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
| | - Markéta Skaličková
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Petr Dytrych
- Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - David Hoskovec
- Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
- Department of Analytical Chemistry, University of Chemistry and Technology, Prague, Czechia
| | - Jan Hajduch
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
- The Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Prague, Czechia
| | - Frédéric Vellieux
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Martina Koziar Vašáková
- Department of Respiratory Medicine, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czechia
| | - Pavel Martásek
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
- Department of Analytical Chemistry, University of Chemistry and Technology, Prague, Czechia
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20
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Wu H, Li YL, Liu PM, Yang JJ. Global status and trends of exosomes in neurodegenerative diseases from 2014 to 2023: a bibliometric and visual analysis. Front Aging Neurosci 2025; 17:1496252. [PMID: 40134534 PMCID: PMC11933124 DOI: 10.3389/fnagi.2025.1496252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 02/25/2025] [Indexed: 03/27/2025] Open
Abstract
Background Neurodegenerative diseases (NDs) are chronic and progressive conditions that significantly impact global public health. Recent years have highlighted exosomes as key mechanisms involved in these diseases. This study aims to visualize and analyze the structure and content of exosomes in NDs based on past research to identify new research ideas and directions. Through bibliometric analysis, we assess the current state of research on exosomes in the field of NDs worldwide over the past decade, highlighting significant findings, major research areas, and emerging trends. Methods Publications on exosomes in NDs research were obtained from the Web of Science Core Collection (WOSCC) database. Eligible literature was analyzed using Bibliometric R, VOSviewer, and Citespace. Results Between 2014 and 2023, 2,393 publications on exosomes in NDs were included in the analysis. The number of relevant publications has been increasing yearly, with China leading in international collaboration, followed by the United States. And China has the largest number of academic scholars as leading and corresponding authors in all the countries, known as the great research society and community. Notable institutions contributing to these publications include Nia, the University of San Francisco California, and Capital Medical University, which rank highly in both publication volume and citations. Dimitrios Kapogiannis is a pivotal figure in the author collaboration network, having produced the highest number of publications (Sato et al., 2011) and amassed 3,921 citations. The journal with the most published articles in this field is The International Journal of Molecular Sciences, which has published 131 articles and received 3,347 citations. A recent analysis of keyword clusters indicates that "Exosome-like liposomes," "Independent mechanisms," and "Therapeutic potential" are emerging research hotspots. Conclusion This is the first bibliometric study to provide a comprehensive summary of the research trends and developments regarding exosomes in NDs studies. Future research in this area may explore the role of mesenchymal stromal cells, microRNAs (miRNAs), and targeted drug delivery systems to further investigate the underlying mechanisms and develop new therapeutics.
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Affiliation(s)
- Hao Wu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yao-lei Li
- National Institutes for Food and Drug Control, Beijing, China
| | - Pan-miao Liu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian-jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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21
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Bai L, Yu L, Ran M, Zhong X, Sun M, Xu M, Wang Y, Yan X, Lee RJ, Tang Y, Xie J. Harnessing the Potential of Exosomes in Therapeutic Interventions for Brain Disorders. Int J Mol Sci 2025; 26:2491. [PMID: 40141135 PMCID: PMC11942545 DOI: 10.3390/ijms26062491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Exosomes, which are nano-sized natural vesicles secreted by cells, are crucial for intercellular communication and interactions, playing a significant role in various physiological and pathological processes. Their characteristics, such as low toxicity and immunogenicity, high biocompatibility, and remarkable drug delivery capabilities-particularly their capacity to traverse the blood-brain barrier-make exosomes highly promising vehicles for drug administration in the treatment of brain disorders. This review provides a comprehensive overview of exosome biogenesis and isolation techniques, strategies for the drug loading and functionalization of exosomes, and exosome-mediated blood-brain barrier penetration mechanisms, with a particular emphasis on recent advances in exosome-based drug delivery for brain disorders. Finally, we address the opportunities and challenges associated with utilizing exosomes as a drug delivery system for the brain, summarizing the barriers to clinical translation and proposing future research directions.
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Affiliation(s)
- Lu Bai
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Leijie Yu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Mengqiong Ran
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Xing Zhong
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Meng Sun
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Minhao Xu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Yu Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Xinlei Yan
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Robert J. Lee
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Yaqin Tang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Jing Xie
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
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22
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Puagsopa J, Tongviseskul N, Jaroentomeechai T, Meksiriporn B. Recent Progress in Developing Extracellular Vesicles as Nanovehicles to Deliver Carbohydrate-Based Therapeutics and Vaccines. Vaccines (Basel) 2025; 13:285. [PMID: 40266147 PMCID: PMC11946770 DOI: 10.3390/vaccines13030285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/22/2025] [Accepted: 03/04/2025] [Indexed: 04/24/2025] Open
Abstract
Cell-derived, nanoscale extracellular vesicles (EVs) have emerged as promising tools in diagnostic, therapeutic, and vaccine applications. Their unique properties including the capability to encapsulate diverse molecular cargo as well as the versatility in surface functionalization make them ideal candidates for safe and effective vehicles to deliver a range of biomolecules including gene editing cassettes, therapeutic proteins, glycans, and glycoconjugate vaccines. In this review, we discuss recent advances in the development of EVs derived from mammalian and bacterial cells for use in a delivery of carbohydrate-based protein therapeutics and vaccines. We highlight key innovations in EVs' molecular design, characterization, and deployment for treating diseases including Alzheimer's disease, infectious diseases, and cancers. We discuss challenges for their clinical translation and provide perspectives for future development of EVs within biopharmaceutical research and the clinical translation landscape.
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Affiliation(s)
- Japigorn Puagsopa
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Niksa Tongviseskul
- Department of Biology, School of Science, King Mongkut’s Institute of Technology Ladkrabang, Bangkok 10520, Thailand;
| | - Thapakorn Jaroentomeechai
- Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark
| | - Bunyarit Meksiriporn
- Department of Biology, School of Science, King Mongkut’s Institute of Technology Ladkrabang, Bangkok 10520, Thailand;
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23
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Wang W, Yin J. Exosomal miR-203 from bone marrow stem cells targets the SOCS3/NF-κB pathway to regulate neuroinflammation in temporal lobe epilepsy. World J Stem Cells 2025; 17:101395. [DOI: 10.4252/wjsc.v17.i2.101395] [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: 11/28/2024] [Revised: 12/27/2024] [Accepted: 02/11/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally, with temporal lobe epilepsy (TLE) being the most common form. Despite advances in antiepileptic drug development, over 30% of patients suffer from drug-resistant epilepsy, which can lead to severe cognitive impairments and adverse psychosocial outcomes.
AIM To explore the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy, providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.
METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each, and the TLE model group was established by injecting kainic acid. BMSCs were isolated from the mice, and exosomes were purified using ultracentrifugation. Exosomal miR-203 was identified and characterized using high-throughput sequencing and quantitative reverse-transcription polymerase chain reaction. The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.
RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice. In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons, resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway, ultimately leading to enhanced secretion of pro-inflammatory cytokines.
CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy. The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway, thus providing a potential avenue for the development of cell-free therapeutics.
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Affiliation(s)
- Wei Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Jian Yin
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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24
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Tew VK, Barathan M, Nordin F, Law JX, Ng MH. Emerging Role of Mesenchymal Stromal Cell and Exosome Therapies in Treating Cognitive Impairment. Pharmaceutics 2025; 17:284. [PMID: 40142948 PMCID: PMC11945939 DOI: 10.3390/pharmaceutics17030284] [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: 11/18/2024] [Revised: 12/27/2024] [Accepted: 01/09/2025] [Indexed: 03/28/2025] Open
Abstract
Cognitive aging, characterized by the gradual decline in cognitive functions such as memory, attention, and problem-solving, significantly impacts daily life. This decline is often accelerated by neurodegenerative diseases, particularly Alzheimer's Disease (AD) and Parkinson's Disease (PD). AD is marked by the accumulation of amyloid-beta plaques and tau tangles, whereas PD involves the degeneration of dopaminergic neurons. Both conditions lead to severe cognitive impairment, greatly diminishing the quality of life for affected individuals. Recent advancements in regenerative medicine have highlighted mesenchymal stromal cells (MSCs) and their derived exosomes as promising therapeutic options. MSCs possess regenerative, neuroprotective, and immunomodulatory properties, which can promote neurogenesis, reduce inflammation, and support neuronal health. Exosomes, nanosized vesicles derived from MSCs, provide an efficient means for delivering bioactive molecules across the blood-brain barrier, targeting the underlying pathologies of AD and PD. While these therapies hold great promise, challenges such as variability in MSC sources, optimal dosing, and effective delivery methods need to be addressed for clinical application. The development of robust protocols, along with rigorous clinical trials, is crucial for validating the safety and efficacy of MSC and exosome therapies. Future research should focus on overcoming these barriers, optimizing treatment strategies, and exploring the integration of MSC and exosome therapies with lifestyle interventions. By addressing these challenges, MSC- and exosome-based therapies could offer transformative solutions for improving outcomes and enhancing the quality of life for individuals affected by cognitive aging and neurodegenerative diseases.
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Affiliation(s)
| | | | | | | | - Min Hwei Ng
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia (F.N.); (J.X.L.)
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25
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Yang L, Li S, Hou C, Wang Z, He W, Zhang W. Recent advances in mRNA-based therapeutics for neurodegenerative diseases and brain tumors. NANOSCALE 2025; 17:3537-3548. [PMID: 39750745 DOI: 10.1039/d4nr04394d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Messenger RNA (mRNA) therapy is an innovative approach that delivers specific protein-coding information. By promoting the ribosomal synthesis of target proteins within cells, it supplements functional or antigenic proteins to treat diseases. Unlike traditional gene therapy, mRNA does not need to enter the cell nucleus, reducing the risks associated with gene integration. Moreover, protein expression levels can be regulated by adjusting the dosage and degradation rates of mRNA. As a new generation gene therapy strategy, mRNA therapy represents the latest advancements and trends in the field. It offers advantages such as precision, safety, and ease of modification. It has been widely used in the prevention of COVID-19. Unlike acute conditions such as cerebral hemorrhage and stroke that often require immediate surgical or interventional treatments, neurodegenerative diseases (NDs) and brain tumors progress relatively slowly and face challenges such as the blood-brain barrier and complex pathogenesis. These characteristics make them particularly suitable for mRNA therapy. With continued research, mRNA-based therapeutics are expected to play a significant role in the prevention and treatment of NDs and brain tumors. This paper reviews the preparation and delivery of mRNA drugs and summarizes the research progress of mRNA gene therapy in treating NDs and brain tumors. It also discusses the current challenges, providing a theoretical basis and reference for future research in this field.
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Affiliation(s)
- Lizhi Yang
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Shuo Li
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Chao Hou
- Department of Ultrasound, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Zihua Wang
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Wen He
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Wei Zhang
- Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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26
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Jang YJ, Kang SJ, Park HS, Lee DH, Kim JH, Kim JE, Kim DI, Chung CH, Yoon JK, Bhang SH. Drug delivery strategies with lipid-based nanoparticles for Alzheimer's disease treatment. J Nanobiotechnology 2025; 23:99. [PMID: 39930497 PMCID: PMC11809104 DOI: 10.1186/s12951-025-03109-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/11/2025] [Indexed: 02/14/2025] Open
Abstract
Alzheimer's disease (AD) is a distinctive form of dementia characterized by age-related cognitive decline and memory impairment. A key hallmark of AD is the irreversible overaccumulation of beta-amyloid (Aβ) in the brain, associated with neuroinflammation and neuronal death. Although Aβ clearance and immunoregulation have been the major therapeutic strategies for AD, highly selective transport across the blood-brain barrier (BBB) negatively affects the delivery efficacy of the drugs without the ability to cross the BBB. In this review, we discuss the potential of lipid-based nanoparticles (LBNs) as promising vehicles for drug delivery in AD treatment. LBNs, composed of phospholipid mono- or bilayer, have attracted attention due to their exceptional cellular penetration capabilities and drug loading capabilities, which also facilitate cargo transcytosis across the BBB. Recent advances in the development and engineering of LBNs overcome the existing limitations of the current clinical approaches for AD treatment by addressing off-target effects and low therapeutic efficacy. Here, we review the transport pathways across the BBB, as well as various types of LBNs for AD therapy, including exosomes, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), to elucidate their distinctive properties, preparation methodologies, and therapeutic efficacy, thereby offering innovative avenues for novel drug development for clinical translation in AD therapy.
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Affiliation(s)
- Young-Ju Jang
- School of Chemical Engineering, Sungkyunkwan University, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
| | - Seong-Jun Kang
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si, 17546, Gyeonggi-do, Republic of Korea
| | - Hyun Su Park
- School of Chemical Engineering, Sungkyunkwan University, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
| | - Dong-Hyun Lee
- School of Chemical Engineering, Sungkyunkwan University, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
| | - Jae Hoon Kim
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si, 17546, Gyeonggi-do, Republic of Korea
| | - Ju-El Kim
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si, 17546, Gyeonggi-do, Republic of Korea
| | - Dong-Ik Kim
- Division of Vascular Surgery, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, 06351, Republic of Korea
| | - Chan-Hwa Chung
- School of Chemical Engineering, Sungkyunkwan University, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
| | - Jeong-Kee Yoon
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si, 17546, Gyeonggi-do, Republic of Korea.
| | - Suk Ho Bhang
- School of Chemical Engineering, Sungkyunkwan University, Suwon-si, 16419, Gyeonggi-do, Republic of Korea.
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27
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Jiang Y, Wei ZY, Song ZF, Yu M, Huang J, Qian HY. Platelet membrane-modified exosomes targeting plaques to activate autophagy in vascular smooth muscle cells for atherosclerotic therapy. Drug Deliv Transl Res 2025:10.1007/s13346-025-01792-1. [PMID: 39873880 DOI: 10.1007/s13346-025-01792-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2025] [Indexed: 01/30/2025]
Abstract
Atherosclerosis is one of the leading causes of ischemic cardiovascular disease worldwide. Recent studies indicated that vascular smooth muscle cells (VSMCs) play an indispensable role in the progression of atherosclerosis. Exosomes derived from mesenchymal stem cells (MSCs) have demonstrated promising clinical applications in the treatment of atherosclerosis. However, there are still challenges and limitations persist in targeted therapy. This study aims to develop a bionic nano-delivery system by fusing platelet membranes with exosomes (MSC-ExoP) and explore the anti-atherosclerosis effect of MSC-ExoP by improving the targeting efficiency and participating in regulating the pathophysiological processes associated with VSMCs. The morphology, particle size, stability, and fusion efficiency of MSC-ExoP were assessed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), immunofluorescence staining, and Western blotting, respectively. MSC-ExoP was administered intravenously into ApoE-/- mice via the tail vein. In vivo, immunofluorescence staining was used to assess the targeting efficacy of MSC-ExoP. The ORO staining, H&E staining, Masson staining, aortic root immunofluorescence staining, and Western blot were utilized to evaluate the VSMC autophagy and anti-atherosclerosis effects of MSC-ExoP. In vitro, the autophagy activation of MSC-ExoP on VSMCs was further assessed by immunofluorescence staining and Western blotting. The effects of MSC-ExoP on VSMCs proliferation, migration, and foam cell formation were detected by EdU experiment, Transwell experiment, wound healing experiment, ORO staining, and BODIPY staining. The TEM revealed that MSC-ExoP retained a ring nanostructure, which was similar to MSC-Exo in morphology. NTA analysis indicated the MSC-ExoP exhibited a slight increase after cell membrane fusion. Besides, the stability analysis of exosomes and MSC-ExoP resulted in no significant changes in particle size. Western blot analysis confirmed that MSC-ExoP simultaneously expressed platelet-specific markers (GPVI, GPIbα, CD62P) and exosome-specific markers (CD81, TSG101, and Alix). In ApoE-/- mice, the immunofluorescence of aorta and its roots was significantly enhanced after injection of DiI-labeled MSC-ExoP, indicating enhanced targeting of MSC-Exo to atherosclerotic plaques by platelets. In vivo experiments demonstrated that MSC-ExoP could significantly suppress the progression of atherosclerosis and reduce the area of atherosclerotic plaques by reducing lipid deposition and necrotic nucleus area and increasing collagen content. In vitro experiments further revealed that the uptake of MSC-ExoP by foam cells significantly increased, and their proliferation, migration, and foam formation were inhibited by autophagy activation. This study demonstrated successful fusion of platelet membranes with exosomes derived from MSCs. MSC-ExoP could significantly improve the targeting efficiency of atherosclerosis and play an anti-atherosclerosis effect by activating VSMC autophagy.
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Affiliation(s)
- Yu Jiang
- Center for Coronary Heart Disease, Department of Cardiology, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037, China
| | - Zhi-Yao Wei
- Center for Coronary Heart Disease, Department of Cardiology, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037, China
| | - Zhi-Feng Song
- Center for Coronary Heart Disease, Department of Cardiology, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037, China
| | - Miao Yu
- Center for Coronary Heart Disease, Department of Cardiology, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037, China
| | - Ji Huang
- Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing, China.
| | - Hai-Yan Qian
- Center for Coronary Heart Disease, Department of Cardiology, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing, 100037, China.
- Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing, China.
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28
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Kim JE, Lee JW, Cha GD, Yoon JK. The Potential of Mesenchymal Stem Cell-Derived Exosomes to Treat Diabetes Mellitus. Biomimetics (Basel) 2025; 10:49. [PMID: 39851765 PMCID: PMC11760843 DOI: 10.3390/biomimetics10010049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 12/27/2024] [Accepted: 12/31/2024] [Indexed: 01/26/2025] Open
Abstract
Diabetes mellitus (DM) is a fatal metabolic disease characterized by persistent hyperglycemia. In recent studies, mesenchymal stem cell (MSC)-derived exosomes, which are being investigated clinically as a cell-free therapy for various diseases, have gained attention due to their biomimetic properties that closely resemble natural cellular communication systems. These MSC-derived exosomes inherit the regenerative and protective effects from MSCs, inducing pancreatic β-cell proliferation and inhibiting apoptosis, as well as ameliorating insulin resistance by suppressing the release of various inflammatory cytokines. Consequently, MSC-derived exosomes have attracted attention as a novel treatment for DM as an alternative to stem cell therapy. In this review, we will introduce the potential of MSC-derived exosomes for the treatment of DM by discussing the studies that have used MSC-derived exosomes to treat DM, which have shown therapeutic effects in both type 1 and type 2 DM.
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Affiliation(s)
| | | | | | - Jeong-Kee Yoon
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si 17546, Gyeonggi-do, Republic of Korea (G.D.C.)
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29
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Lerussi G, Villagrasa-Araya V, Moltó-Abad M, del Toro M, Pintos-Morell G, Seras-Franzoso J, Abasolo I. Extracellular Vesicles as Tools for Crossing the Blood-Brain Barrier to Treat Lysosomal Storage Diseases. Life (Basel) 2025; 15:70. [PMID: 39860010 PMCID: PMC11766495 DOI: 10.3390/life15010070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/03/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Extracellular vesicles (EVs) are nanosized, membrane-bound structures that have emerged as promising tools for drug delivery, especially in the treatment of lysosomal storage disorders (LSDs) with central nervous system (CNS) involvement. This review highlights the unique properties of EVs, such as their biocompatibility, capacity to cross the blood-brain barrier (BBB), and potential for therapeutic cargo loading, including that of enzymes and genetic material. Current therapies for LSDs, like enzyme replacement therapy (ERT), often fail to address neurological symptoms due to their inability to cross the BBB. EVs offer a viable alternative, allowing for targeted delivery to the CNS and improving therapeutic outcomes. We discuss recent advancements in the engineering and modification of EVs to enhance targeting, circulation time and cargo stability, and provide a detailed overview of their application in LSDs, such as Gaucher and Fabry diseases, and Sanfilippo syndrome. Despite their potential, challenges remain in scaling production, ensuring isolation purity, and meeting regulatory requirements. Future developments will focus on overcoming these barriers, paving the way for the clinical translation of EV-based therapies in LSDs and other CNS disorders.
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Affiliation(s)
- Giovanni Lerussi
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
| | - Verónica Villagrasa-Araya
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
- Institute of Advanced Chemistry of Catalonia (IQAC), Centro Superior de Investigaciones Científicas (CSIC), 08034 Barcelona, Spain
| | - Marc Moltó-Abad
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
| | - Mireia del Toro
- Pediatric Neurology Unit, Hospital Universitari Vall d’Hebron and MetabERN, 08035 Barcelona, Spain;
- Networking Research Center on Rare Diseases (CIBERER), 08035 Barcelona, Spain
| | - Guillem Pintos-Morell
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
| | - Joaquin Seras-Franzoso
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
| | - Ibane Abasolo
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
- Institute of Advanced Chemistry of Catalonia (IQAC), Centro Superior de Investigaciones Científicas (CSIC), 08034 Barcelona, Spain
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Satyanarayanan SK, Han Z, Xiao J, Yuan Q, Yung WH, Ke Y, Chang RCC, Zhu MH, Su H, Su KP, Qin D, Lee SMY. Frontiers of Neurodegenerative Disease Treatment: Targeting Immune Cells in Brain Border Regions. Brain Behav Immun 2025; 123:483-499. [PMID: 39378973 DOI: 10.1016/j.bbi.2024.10.007] [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: 05/03/2024] [Revised: 09/15/2024] [Accepted: 10/05/2024] [Indexed: 10/10/2024] Open
Abstract
Neurodegenerative diseases (NDs) demonstrate a complex interaction with the immune system, challenging the traditional view of the brain as an "immune-privileged" organ. Microglia were once considered the sole guardians of the brain's immune response. However, recent research has revealed the critical role of peripheral immune cells located in key brain regions like the meninges, choroid plexus, and perivascular spaces. These previously overlooked cells are now recognized as contributors to the development and progression of NDs. This newfound understanding opens doors for pioneering therapeutic strategies. By targeting these peripheral immune cells, we may be able to modulate the brain's immune environment, offering an alternative approach to treat NDs and circumvent the challenges posed by the blood-brain barrier. This comprehensive review will scrutinize the latest findings on the complex interactions between these peripheral immune cells and NDs. It will also critically assess the prospects of targeting these cells as a ground-breaking therapeutic avenue for these debilitating disorders.
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Affiliation(s)
- Senthil Kumaran Satyanarayanan
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong Science Park, Hong Kong, China
| | - Zixu Han
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong Science Park, Hong Kong, China
| | - Jingwei Xiao
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong Science Park, Hong Kong, China
| | - Qiuju Yuan
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong Science Park, Hong Kong, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Wing Ho Yung
- Department of Neuroscience, City University of Hong Kong, Hong Kong, China
| | - Ya Ke
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Raymond Chuen-Chung Chang
- Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Faculty of Medicine Building, Hong Kong, China
| | - Maria Huachen Zhu
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, Hong Kong, China
| | - Kuan-Pin Su
- An-Nan Hospital, China Medical University, Tainan, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; Mind-Body Interface Research Center (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
| | - Dajiang Qin
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong Science Park, Hong Kong, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
| | - Suki Man Yan Lee
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong Science Park, Hong Kong, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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Wang N, Ma F, Song H, He N, Zhang H, Li J, Liu Q, Xu C. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Regenerative Applications and Radiotherapy. Cell Transplant 2025; 34:9636897241311019. [PMID: 39780320 PMCID: PMC11713979 DOI: 10.1177/09636897241311019] [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: 09/26/2024] [Revised: 12/12/2024] [Accepted: 12/15/2024] [Indexed: 01/11/2025] Open
Abstract
Tissue repair is an extremely crucial part of clinical treatment. During the course of disease treatment, surgery, chemotherapy, and radiotherapy cause tissue damage. On the other hand, Normal tissue from accidental or therapeutic exposure to high-dose radiation can cause severe tissue damage. There is an urgent need for developing medical countermeasures against radiation injury for tissue repair. Tissue repair involves the regeneration, proliferation, differentiation, and migration of tissue cells; imbalance of local tissue homeostasis, progressive chronic inflammation; decreased cell activity and stem cell function; and wound healing. Although many clinical treatments are currently available for tissue repair, they are expensive. The long recovery time and some unavoidable complications such as cell damage and the inflammatory reaction caused by radiotherapy have led to unsatisfactory results. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have similar tissue repair functions as MSCs. In tissue damage, EVs can be used as an alternative to stem cell therapy, thereby avoiding related complications such as immunological rejection. EVs play a major role in regulating tissue damage, anti-inflammation, pro-proliferation, and immune response, thus providing a diversified and efficient solution for the repair of disease- and radiotherapy-induced tissue damage. This article reviews the research progress of mesenchymal stem cell-derived EVs in promoting the repair of tissue including heart, lung, liver, intestine, skin, blood system, central nervous system, and tissue damage caused by radiotherapy, thereby aiming to offer new directions and ideas for the radiotherapy and regenerative applications.
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Affiliation(s)
- Ning Wang
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
| | - Feifei Ma
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
| | - Huijuan Song
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Ningning He
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Huanteng Zhang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Jianguo Li
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
| | - Qiang Liu
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Chang Xu
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
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Lotfi M, Baharara J, Shahrokhabadi KN, Khorshid P. Examining the Synergic Effect of Exosomes Derived from Mouse Mesenchymal Stem Cells and Low-frequency Electromagnetic Field on Chondrogenic Differentiation. Curr Stem Cell Res Ther 2025; 20:336-349. [PMID: 40351083 DOI: 10.2174/011574888x314834240628110545] [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: 04/03/2024] [Revised: 05/20/2024] [Accepted: 05/28/2024] [Indexed: 05/14/2025]
Abstract
BACKGROUND Cartilage has intrinsically limited healing power, and regeneration of cartilage damages has remained a challenge. Secreted products of mesenchymal stem cells have shown a new therapeutic strategies for cartilage injuries. Also it has been observed that low frequency electromagnetic field plays a key role in biological processes. OBJECTIVE This research was performed to investigate the synergic effect of mesenchymal stem cell-derived exosomes and low frequency electromagnetic field on chondrogenic differentiation. METHODS In this in vitro study, mesenchymal stem cell-derived exosomes were identified using AFM, SEM, TEM microscopy, and DLS method. Cells were treated in chondrogenic medium by exosomes, low frequency electromagnetic field, and the synergy of both. The cell survival was examined using MTT and Annexin methods, and cartilage differentiation was confirmed by Alcian blue staining. The expression of Sox-9, Acan, Col 2a1 and Col 10a1 genes was examined via Real- Time PCR technique on day 14 post-treatment. RESULTS The results confirmed the presence of exosomes with an approximate size of less than 100 nm. The results of Alcian blue revealed greater expression of glycosaminoglycans in the synergic treatment group compared to the other groups. Real-time PCR showed a significant increase in the expression of Sox-9, Acan, and Col 2a1 genes, as well as a significant reduction of Col 10a1 gene expression in the synergic treatment group compared to other groups. CONCLUSION This study indicated that the synergic effect of exosome and low-frequency electromagnetic fields would lead to enhanced chondrogenic differentiation, which can be further explored in future clinical studies.
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Affiliation(s)
- Maryam Lotfi
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Javad Baharara
- Department of Biology & Research Center for Animal Development Applied Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | | | - Pejman Khorshid
- Department of Physics, Mashhad Branch, Islamic Azad University, Mashhad, Iran
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Khosroshahi PA, Ghanbari M. MicroRNA dysregulation in glutamate and dopamine pathways of schizophrenia: From molecular pathways to diagnostic and therapeutic approaches. Prog Neuropsychopharmacol Biol Psychiatry 2024; 135:111081. [PMID: 39002925 DOI: 10.1016/j.pnpbp.2024.111081] [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: 12/01/2023] [Revised: 06/28/2024] [Accepted: 07/07/2024] [Indexed: 07/15/2024]
Abstract
Schizophrenia is a complex psychiatric disorder, and genetic and environmental factors have been implicated in its development. Dysregulated glutamatergic and dopaminergic transmission pathways are involved in schizophrenia development. Besides genetic mutations, epigenetic dysregulation has a considerable role in dysregulating molecular pathways involved in schizophrenia. MicroRNAs (miRNAs) are small, non-coding RNAs that target specific mRNAs and inhibit their translation into proteins. As epigenetic factors, miRNAs regulate many genes involved in glutamate and dopamine signaling pathways; thereby, their dysregulation can contribute to the development of schizophrenia. Secretion of specific miRNAs from damaged cells into body fluids can make them one of the ideal non-invasive biomarkers in the early diagnosis of schizophrenia. Also, understanding the molecular mechanisms of miRNAs in schizophrenia pathogenesis can pave the way for developing novel treatments for patients with schizophrenia. In this study, we reviewed the glutamatergic and dopaminergic pathophysiology and highlighted the role of miRNA dysregulation in schizophrenia development. Besides, we shed light on the significance of circulating miRNAs for schizophrenia diagnosis and the recent findings on the miRNA-based treatment for schizophrenia.
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Affiliation(s)
| | - Mohammad Ghanbari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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Yang H, Tan H, Wen H, Xin P, Liu Y, Deng Z, Xu Y, Gao F, Zhang L, Ye Z, Zhang Z, Chen Y, Wang Y, Sun J, Lam JWY, Zhao Z, Kwok RTK, Qiu Z, Tang BZ. Recent Progress in Nanomedicine for the Diagnosis and Treatment of Alzheimer's Diseases. ACS NANO 2024; 18:33792-33826. [PMID: 39625718 DOI: 10.1021/acsnano.4c11966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that causes memory loss and progressive and permanent deterioration of cognitive function. The most challenging issue in combating AD is its complicated pathogenesis, which includes the deposition of amyloid β (Aβ) plaques, intracellular hyperphosphorylated tau protein, neurofibrillary tangles (NFT), etc. Despite rapid advancements in mechanistic research and drug development for AD, the currently developed drugs only improve cognitive ability and temporarily relieve symptoms but cannot prevent the development of AD. Moreover, the blood-brain barrier (BBB) creates a huge barrier to drug delivery in the brain. Therefore, effective diagnostic tools and treatments are urgently needed. In recent years, nanomedicine has provided opportunities to overcome the challenges and limitations associated with traditional diagnostics or treatments. Various types of nanoparticles (NPs) play an essential role in nanomedicine for the diagnosis and treatment of AD, acting as drug carriers to improve targeting and bioavailability across/bypass the BBB or acting as drugs directly on AD lesions. This review categorizes different types of NPs and summarizes their applications in nanomedicine for the diagnosis and treatment of AD. It also discusses the challenges associated with clinical applications and explores the latest developments and prospects of nanomedicine for AD.
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Affiliation(s)
- Han Yang
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
- Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Division of Life Science, State Key Laboratory of Molecular Neuroscience, and Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong China
| | - Haozhe Tan
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Haifei Wen
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Peikun Xin
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Yanling Liu
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Ziwei Deng
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Yanning Xu
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Feng Gao
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Liping Zhang
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Ziyue Ye
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Zicong Zhang
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Yunhao Chen
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Yueze Wang
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Jianwei Sun
- Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Division of Life Science, State Key Laboratory of Molecular Neuroscience, and Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong China
| | - Jacky W Y Lam
- Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Division of Life Science, State Key Laboratory of Molecular Neuroscience, and Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong China
| | - Zheng Zhao
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Ryan T K Kwok
- Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Division of Life Science, State Key Laboratory of Molecular Neuroscience, and Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong China
| | - Zijie Qiu
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
| | - Ben Zhong Tang
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong 518172, P.R. China
- Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Division of Life Science, State Key Laboratory of Molecular Neuroscience, and Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong China
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Chen H, Deng C, Meng Z, Zhu M, Yang R, Yuan J, Meng S. Combined Catalpol and Tetramethylpyrazine Promote Axonal Plasticity in Alzheimer's Disease by Inducing Astrocytes to Secrete Exosomes Carrying CDK5 mRNA and Regulating STAT3 Phosphorylation. Mol Neurobiol 2024; 61:10770-10791. [PMID: 38789892 DOI: 10.1007/s12035-024-04251-z] [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: 07/22/2023] [Accepted: 05/13/2024] [Indexed: 05/26/2024]
Abstract
Alzheimer's disease (AD) is a common progressive degenerative disease of the central nervous system in aging populations. This study aimed to investigate the effects of combined catalpol and tetramethylpyrazine (CT) in promoting axonal plasticity in AD and the potential underlying mechanism. Astrocytes were treated with different concentrations of compatible CT. Exosomes were collected and subjected to sequencing analysis, which was followed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes. Amyloid precursor protein/presenilin 1 (APP/PS1) double-transfected male mice were used as the in vivo AD models. Astrocyte-derived exosomes that were transfected with cyclin-dependent kinase 5 (CDK5) or CT treatment were injected into the tail vein of mice. The levels of CDK5, synaptic plasticity marker protein neurofilament 200 (NF200), and growth-associated protein 43 (GAP-43) in the hippocampus of mice were compared in each group. Immunofluorescence staining was used to detect the localization of STAT3 and to visualize synaptic morphology via β-tubulin-III (TUBB3). Astrocyte-derived exosomes transfected with siCDK5 or treated with CT were co-cultured with HT-22 cells, which were untransfected or silenced for signal transducer and activator of transcription 3 (STAT3). Amyloid β-protein (Aβ)1-42 was induced in the in vitro AD models. The viability, apoptosis, and expression levels of NF200 and GAP-43 proteins in the hippocampal neurons of each group were compared. In total, 166 differentially expressed genes in CT-induced astrocyte-derived exosomes were included in the KEGG analysis, and they were found to be enriched in 12 pathways, mainly in axon guidance. CT treatment significantly increased the level of CDK5 mRNA in astrocyte-derived exosomes-these exosomes restored CDK5 mRNA and protein levels in the hippocampus of the in vivo AD model mice and the in vitro AD model; promoted p-STAT3 (Ser727), NF200 and GAP-43 proteins; and promoted the regeneration and extension of neuronal synapses. Silencing of CDK5 blocked both neuronal protection as well as induction of axonal plasticity in AD by CT-treated exosomes in vitro and in vivo. Moreover, silencing of STAT3 blocked both neuronal protection as well as induction of axonal plasticity in AD caused by CDK5 overexpression or CT-treated astrocyte-induced exosomes. CT promotes axonal plasticity in AD by inducing astrocytes to secrete exosomes carrying CDK5 mRNA and regulating STAT3 (Ser727) phosphorylation.
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Affiliation(s)
- Huize Chen
- Department of Traditional Chinese Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Xuhui District, 600 Yishan Road, Shanghai, 200233, China
| | - Chujun Deng
- Department of Traditional Chinese Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Xuhui District, 600 Yishan Road, Shanghai, 200233, China
| | - Zeyu Meng
- Second Clinical Medicine College of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Mengting Zhu
- Graduate School of Jiangxi, University of Traditional Chinese Medicine, Nanchang, China
| | - Ruoyu Yang
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Yuan
- Department of Traditional Chinese Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Xuhui District, 600 Yishan Road, Shanghai, 200233, China
| | - Shengxi Meng
- Department of Traditional Chinese Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Xuhui District, 600 Yishan Road, Shanghai, 200233, China.
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Li J, Wang Y, Zhang Y, Liu M, Rong X, Jiang J. Therapeutic potential and mechanisms of stem cells in major depressive disorder: a comprehensive review. Front Pharmacol 2024; 15:1476558. [PMID: 39654612 PMCID: PMC11625547 DOI: 10.3389/fphar.2024.1476558] [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: 08/06/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Depression is a common affective disorder characterized by persistent low mood, diminished interest or pleasure in normally enjoyable activities, disturbances in sleep patterns, and suicidal ideation. Conventional treatments often yield unsatisfactory results and are associated with several adverse effects. However, emerging literature has highlighted the potential of stem cell (SC) transplantation as a promising avenue for treating depression owing to its favorable anti-inflammatory and neurotrophic properties. This review summarizes the therapeutic effects and underlying mechanisms associated with SC transplantation in depression, offering a conceptual framework for the future application of SCs in the clinical treatment of depression.
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Affiliation(s)
| | | | | | | | | | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun, China
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Yadav S, Maity P, Kapat K. The Opportunities and Challenges of Mesenchymal Stem Cells-Derived Exosomes in Theranostics and Regenerative Medicine. Cells 2024; 13:1956. [PMID: 39682706 PMCID: PMC11640604 DOI: 10.3390/cells13231956] [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: 10/25/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.
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Affiliation(s)
- Sachin Yadav
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
| | - Pritiprasanna Maity
- School of Medicine, University of California Riverside, Riverside, CA 92525, USA
| | - Kausik Kapat
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
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38
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Zhao S, Di Y, Fan H, Xu C, Li H, Wang Y, Wang W, Li C, Wang J. Targeted delivery of extracellular vesicles: the mechanisms, techniques and therapeutic applications. MOLECULAR BIOMEDICINE 2024; 5:60. [PMID: 39567444 PMCID: PMC11579273 DOI: 10.1186/s43556-024-00230-x] [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: 08/14/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/22/2024] Open
Abstract
Extracellular vesicles (EVs) are cell-derived vesicles with a phospholipid bilayer measuring 50-150 nm in diameter with demonstrated therapeutic potentials. Limitations such as the natural biodistribution (mainly concentrated in the liver and spleen) and short plasma half-life of EVs present significant challenges to their clinical translation. In recent years, growing research indicated that engineered EVs with enhanced targeting to lesion sites have markedly promoted therapeutic efficacy. However, there is a dearth of systematic knowledge on the recent advances in engineering EVs for targeted delivery. Herein, we provide an overview of the targeting mechanisms, engineering techniques, and clinical translations of natural and engineered EVs in therapeutic applications. Enrichment of EVs at lesion sites may be achieved through the recognition of tissue markers, pathological changes, and the circumvention of mononuclear phagocyte system (MPS). Alternatively, external stimuli, including magnetic fields and ultrasound, may also be employed. EV engineering techniques that fulfill targeting functions includes genetic engineering, membrane fusion, chemical modification and physical modification. A comparative statistical analysis was conducted to elucidate the discrepancies between the diverse techniques on size, morphology, stability, targeting and therapeutic efficacy in vitro and in vivo. Additionally, a summary of the registered clinical trials utilizing EVs from 2010 to 2023 has been provided, with a full discussion on the perspectives. This review provides a comprehensive overview of the mechanisms and techniques associated with targeted delivery of EVs in therapeutic applications to advocate further explorations of engineered EVs and accelerate their clinical applications.
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Affiliation(s)
- Shuang Zhao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yunfeng Di
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Huilan Fan
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Chengyan Xu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Haijing Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yong Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100029, China
- Key Laboratory of Traditional Chinese Medicine Syndrome and Formula, Ministry of Education, Beijing, 100029, China
| | - Wei Wang
- Key Laboratory of Traditional Chinese Medicine Syndrome and Formula, Ministry of Education, Beijing, 100029, China
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chun Li
- Key Laboratory of Traditional Chinese Medicine Syndrome and Formula, Ministry of Education, Beijing, 100029, China
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
- Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jingyu Wang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Li C, Yang Y, Luo S, Qiu W, Wang X, Ge W. GNG5 is a novel regulator of Aβ42 production in Alzheimer's disease. Cell Death Dis 2024; 15:815. [PMID: 39528445 PMCID: PMC11554683 DOI: 10.1038/s41419-024-07218-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/27/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
The therapeutic options for Alzheimer's disease (AD) are limited, underscoring the critical need for finding an effective regulator of Aβ42 production. In this study, with 489 human postmortem brains, we revealed that homotrimer G protein subunit gamma 5 (GNG5) expression is upregulated in the hippocampal-entorhinal region of pathological AD compared with normal controls, and is positively correlated with Aβ pathology. In vivo and in vitro experiments confirm that increased GNG5 significantly promotes Aβ pathology and Aβ42 production. Mechanically, GNG5 regulates the cleavage preference of γ-secretase towards Aβ42 by directly interacting with the γ-secretase catalytic subunit presenilin 1 (PS1). Moreover, excessive GNG5 increases the protein levels and the activation of Rab5, leading to the increased number of early endosomes, the major cellular organelle for production of Aβ42. Furthermore, immunoprecipitation and immunofluorescence revealed co-interaction of Aβ42 with GPCR family CXCR2, which is known as the receptor for IL-8, thus facilitating the dissociation of G-proteins βγ from α subunits. Treatment of Aβ42 in neurons combined with structure prediction indicated Aβ42 oligomers as a new ligand of CXCR2, upregulating γ subunit GNG5 protein levels. The co-localizations of GNG5 and PS1, CXCR2 and Aβ42 were verified in eight human brain regions. Besides, GNG5 is significantly reduced in extracellular vesicles (EVs) derived from cerebral cortex or serum of AD patients compared with healthy cognition controls. In brief, GNG5 is a novel regulator of Aβ42 production, suggesting its clinical potential as a diagnosis biomarker and the therapeutic target for AD. The GNG5 content in EVs derived from serum and brain tissue of patients with AD significantly reduced. The GNG5 expression in the hippocampal-entorhinal neurons of donors with pathological AD significantly increased, and can exist in homotrimer subtypes. GNG5 expression positively correlates with Aβ pathology and Aβ42 production. Homotrimer-GNG5 binds to the γ-secretase catalytic subunit PS1 and preferentially generates Aβ42 in early endosome. GNG5 leads to enhanced Rab5 protein and activation levels, increased number of early endosome, promoting Aβ42 production. Further, Aβ42 binds to CXCR2 to upregulate GNG5 levels in a feedback loop.
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Affiliation(s)
- Chunyuan Li
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yan Yang
- The State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Shiqi Luo
- The State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Wenying Qiu
- Institute of Basic Medical Sciences, Neuroscience Center, National Human Brain Bank for Development and Function, Chinese Academy of Medical Sciences, Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xia Wang
- The State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
| | - Wei Ge
- The State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
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Rahnama M, Heidari M, Poursalehi Z, Golchin A. Global Trends of Exosomes Application in Clinical Trials: A Scoping Review. Stem Cell Rev Rep 2024; 20:2165-2193. [PMID: 39340738 DOI: 10.1007/s12015-024-10791-7] [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] [Accepted: 09/19/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Exosomes, nano-sized extracellular vesicles, have emerged as a promising tool for the diagnosis and treatment of various intractable diseases, including chronic wounds and cancers. As our understanding of exosomes continues to grow, their potential as a powerful therapeutic modality in medicine is also expanding. This systematic review aims to examine the progress of exosome-based clinical trials and provide a comprehensive overview of the therapeutic perspectives of exosomes. METHODS This systematic review strictly follows PRISMA guidelines and has been registered in PROSPERO, the International Prospective Register of Systematic Reviews. It encompasses articles from January 2000 to January 2023, sourced from bibliographic databases, with targeted search terms targeting exosome applications in clinical trials. During the screening process, strict inclusion and exclusion criteria were applied, including a focus on clinical trials utilizing different cell-derived exosomes for therapeutic purposes. RESULTS Among the 522 publications initially identified, only 10 studies met the stringent eligibility criteria after meticulous screening. The selection process involved systematically excluding duplicates and irrelevant articles to provide a transparent overview. CONCLUSION According to our systematic review, exosomes have promising applications in a variety of medical fields, including cell-free therapies and drug delivery systems for treating a variety of diseases, especially cancers and chronic wounds. To ensure safety, potency, and broader clinical applications, further optimization of exosome extraction, loading, targeting, and administration is necessary. While cell-based therapeutics are increasingly utilizing exosomes, this field is still in its infancy, and ongoing clinical trials will provide valuable insights into the clinical utility of exosomes.
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Affiliation(s)
- Maryam Rahnama
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Heidari
- Department of Biostatistics and Epidemiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zahra Poursalehi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ali Golchin
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran.
- Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Zhao W, Erhan D, Liu S, Zhang L, Hai C, Zhang Y, Li H, Wang H, Wang C. Adipose-derived stem cells exosomal circHIPK3 protects ovarian function by regulating MAPK signaling. Indian J Pharmacol 2024; 56:411-419. [PMID: 39973830 PMCID: PMC11913337 DOI: 10.4103/ijp.ijp_499_24] [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: 06/11/2024] [Revised: 08/28/2024] [Accepted: 12/19/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Exosomes derived from adipose-derived stem cells (ADSCs) have garnered significant attention for their therapeutic potential in various diseases. These vesicles are capable of transporting bioactive molecules such as noncoding RNAs and proteins. Among these noncoding RNAs, circular RNAs (circRNAs) are characterized as end-to-end circular structures, which are notably enriched within exosomes. OBJECTIVE This study aims to investigate the impact of the circHIPK3 delivered via ADSC-derived exosomes on ovarian aging. MATERIALS AND METHODS ADSCs were isolated, and exosomes were obtained from a cell culture medium. The exosomes were labeled with PKH26, and uptake by primary granulosa cells (pGCs) was detected. ADSCs were transfected with circHIPK3 siRNAs, and the exosomes were isolated for the treatment of aging female mice. Ovary weight was recorded, and HE staining, Masson's trichrome, and TUNEL staining were performed to detect tissue morphology and apoptosis in ovary tissues. In addition, the senescence and apoptosis of pGCs were evaluated using the S-β-gal staining kit and Annexin V/PI detection kit. Further experiments included immunoprecipitation and RNA pulldown, determined the ubiquitination of p38 protein under circHIPK3 alteration. RESULTS Results showed that ADSC-derived exosomes effectively delivered circHIPK3 to pGCs. Treatment with these exosomes significantly increased ovary weight and enhanced follicular development in aged mice. Conversely, the depletion of circHIPK3 reversed these effects, promoting cell apoptosis. ADSC-derived exosomes also mitigated senescence and apoptosis in pGCs, while circHIPK3 depletion hindered these benefits. CONCLUSION Exosomal circHIPK3 modulated the ubiquitination of p38 in pGCs to improve ovarian function in aging mice and to promote pGC cell viability.
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Affiliation(s)
- Wei Zhao
- Department of Reproductive Center, Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
- The Obstetric and Gynecologic, Grand Hospital of Shuozhou, Shanxi Shuozhou, China
| | - Da Erhan
- The Second Xiangya Hospital, Central South University, Hunan Changsha, China
| | - Shujun Liu
- Department of Science and Education Section, Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
| | - Liyan Zhang
- Department of Reproductive Center, Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
| | - Caizhu Hai
- Department of Reproductive Center, Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
| | - Yanan Zhang
- Department Of Gynecology, Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
| | - Haiyan Li
- Department Of Gynecology, Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
| | - Hongwu Wang
- Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
| | - Caisheng Wang
- Xilingol League Central Hospital, Inner Mongolia Xilingol League, China
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Ale Y, Nainwal N. Exosomes as nanocarrier for Neurotherapy: Journey from application to challenges. J Drug Deliv Sci Technol 2024; 101:106312. [DOI: 10.1016/j.jddst.2024.106312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Zhang Y, Wu D, Zhou C, Bai M, Wan Y, Zheng Q, Fan Z, Wang X, Yang C. Engineered extracellular vesicles for tissue repair and regeneration. BURNS & TRAUMA 2024; 12:tkae062. [PMID: 39439545 PMCID: PMC11495891 DOI: 10.1093/burnst/tkae062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/12/2024] [Accepted: 09/21/2024] [Indexed: 10/25/2024]
Abstract
Extracellular vesicles (EVs) are heterogeneous membrane-like vesicles secreted by living cells that are involved in many physiological and pathological processes and act as intermediaries of intercellular communication and molecular transfer. Recent studies have shown that EVs from specific sources regulate tissue repair and regeneration by delivering proteins, lipids, and nucleic acids to target cells as signaling molecules. Nanotechnology breakthroughs have facilitated the development and exploration of engineered EVs for tissue repair. Enhancements through gene editing, surface modification, and content modification have further improved their therapeutic efficacy. This review summarizes the potential of EVs in tissue repair and regeneration, their mechanisms of action, and their research progress in regenerative medicine. This review highlights their design logic through typical examples and explores the development prospects of EVs in tissue repair. The aim of this review is to provide new insights into the design of EVs for tissue repair and regeneration applications, thereby expanding their use in regenerative medicine.
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Affiliation(s)
- Yan Zhang
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
- School of Public Health, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Dan Wu
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Chen Zhou
- Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, No. 3025 Shennan Middle Road, Futian District, Shenzhen, China
| | - Muran Bai
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Yucheng Wan
- Hospital of Stomatology, Zunyi Medical University, No. 89, Wujiang East Road, Xinpu New District, Zunyi City, Guizhou Province, China
| | - Qing Zheng
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Zhijin Fan
- Institute for Engineering Medicine, Kunming Medical University, No. 1168 Chunrong West Road, Yuhua Street, Chenggong District, Kunming City, Yunnan Province China
| | - Xianwen Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Medical University, No.81 Meishan Road, Shushan District, Hefei 230032, China
| | - Chun Yang
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
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Jin B, Liao Y, Ding Z, Zou R, Xu F, Li Y, Cheng B, Niu L. The role of biophysical cues and their modulated exosomes in dental diseases: from mechanism to therapy. Stem Cell Res Ther 2024; 15:373. [PMID: 39427216 PMCID: PMC11491033 DOI: 10.1186/s13287-024-03990-z] [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: 06/19/2024] [Accepted: 10/09/2024] [Indexed: 10/21/2024] Open
Abstract
Dental diseases such as caries and periodontitis have been common public health problems. Dental disease treatment can be achieved through stem cell-based dental regeneration. Biophysical cues determine the fate of stem cells and govern the success of dental regeneration. Some studies have manifested exosomes derived from stem cells could not only inherit biophysical signals in microenvironment but also evade some issues in the treatment with stem cells. Nowadays, biophysical cue-regulated exosomes become another promising therapy in dental regenerative medicine. However, methods to improve the efficacy of exosome therapy and the underlying mechanisms are still unresolved. In this review, the association between biophysical cues and dental diseases was summarized. We retrospected the role of exosomes regulated by biophysical cues in curing dental diseases and promoting dental regeneration. Our research also delved into the mechanisms by which biophysical cues control the biogenesis, release, and uptake of exosomes, as well as potential methods to enhance the effectiveness of exosomes. The aim of this review was to underscore the important place biophysical cue-regulated exosomes occupy in the realm of dentistry, and to explore novel targets for dental diseases.
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Affiliation(s)
- Bilun Jin
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Yuxin Liao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Zhaojing Ding
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Rui Zou
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Feng Xu
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Ye Li
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
| | - Bo Cheng
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
| | - Lin Niu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
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Shanmugam I, Radhakrishnan S, Santosh S, Ramnath A, Anil M, Devarajan Y, Maheswaran S, Narayanan V, Pitchaimani A. Emerging role and translational potential of small extracellular vesicles in neuroscience. Life Sci 2024; 355:122987. [PMID: 39151884 DOI: 10.1016/j.lfs.2024.122987] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Small extracellular vesicles (sEV) are endogenous lipid-bound membrane vesicles secreted by both prokaryotic and eukaryotic cells into the extracellular environment, performs several biological functions such as cell-cell communication, transfer of proteins, mRNA, and ncRNA to target cells in distant sites. Due to their role in molecular pathogenesis and its potential to deliver biological cargo to target cells, it has become a prominent area of interest in recent research in the field of Neuroscience. However, their role in neurological disorders, like neurodegenerative diseases is more complex and still unaddressed. Thus, this review focuses on the role of sEV in neurodegenerative and neurodevelopmental diseases, including their biogenesis, classification, and pathogenesis, with translational advantages and limitations in the area of neurobiology.
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Affiliation(s)
- Iswarya Shanmugam
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Sivani Radhakrishnan
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Shradha Santosh
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Akansha Ramnath
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Meghna Anil
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Yogesh Devarajan
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Saravanakumar Maheswaran
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Vaibav Narayanan
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Arunkumar Pitchaimani
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India.
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Abid AI, Conzatti G, Toti F, Anton N, Vandamme T. Mesenchymal stem cell-derived exosomes as cell free nanotherapeutics and nanocarriers. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 61:102769. [PMID: 38914247 DOI: 10.1016/j.nano.2024.102769] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/18/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Many strategies for regenerating the damaged tissues or degenerating cells are employed in regenerative medicine. Stem cell technology is a modern strategy of the recent approaches, particularly the use of mesenchymal stem cells (MCSs). The ability of MSCs to differentiate as well as their characteristic behaviour as paracrine effector has established them as key elements in tissue repair. Recently, extracellular vesicles (EVs) shed by MSCs have emerged as a promising cell free therapy. This comprehensive review encompasses MSCs-derived exosomes and their therapeutic potential as nanotherapeutics. We also discuss their potency as drug delivery nano-carriers in comparison with liposomes. A better knowledge of EVs behaviour in vivo and of their mechanism of action are key to determine parameters of an optimal formulation in pilot studies and to establish industrial processes.
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Affiliation(s)
- Ali Imran Abid
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France
| | - Guillaume Conzatti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
| | - Florence Toti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Nicolas Anton
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Thierry Vandamme
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
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Zhang W, Uyemura R, Zhong K, Guo R, Zhong L. Current Advances and Future Perspectives on Mesenchymal Stem Cell-Derived Extracellular Vesicles in Alzheimer's Disease. Aging Dis 2024; 15:2015-2027. [PMID: 38270122 PMCID: PMC11346404 DOI: 10.14336/ad.2023.1206] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/06/2023] [Indexed: 01/26/2024] Open
Abstract
The incidence of Alzheimer's disease (AD) has been increasing in recent years as the world's population ages, which poses a significant challenge to public health. Due to the complexity of pathogenesis of AD, currently there is no effective treatment for it. In recent years, cell and gene therapy has attracted widespread attention in the treatment of neurodegenerative diseases. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent a novel cell-free therapy with numerous advantages over cell-based therapies owing to their low immunogenicity and high safety profile. We summarize recent progress in the application of EVs for treating AD and the specific mechanisms and outline the underlying mechanisms. We also explore various methods for optimizing the function of MSC-EVs, including gene editing, modifying stem cell culture conditions and peptide modification. In addition, we discuss the therapeutic potentials of MSC-EVs, as well as the obstacles that currently impede their clinical utilization.
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Affiliation(s)
- Wenjing Zhang
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Russell Uyemura
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766, USA
| | - Kun Zhong
- American Center of Stem Cell Research and Regenerative Medicine, Farmington Hills, Michigan 48336, USA
| | - Rui Guo
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Li Zhong
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766, USA
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Deng H, Zhao J, Li J, Chen C, Hu Z, Wu X, Ge L. Therapeutic Efficacy of Extracellular Vesicles Derived from Stem Cell for Alzheimer's Disease: A Meta-Analysis Study. FRONT BIOSCI-LANDMRK 2024; 29:340. [PMID: 39344329 DOI: 10.31083/j.fbl2909340] [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: 06/24/2024] [Revised: 07/29/2024] [Accepted: 08/06/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) poses a significant public health challenge, increasingly affecting patients' finances, mental health, and functional abilities as the global population ages. Stem cell-derived extracellular vesicles (SC-EVs) have emerged as a promising cell-free therapeutic approach for AD, although their precise mechanisms remain unclear. This meta-analysis aims to evaluate the effectiveness of SC-EVs in treating AD. METHODS We systematically searched PubMed, EMBASE, and Web of Science databases up to December 31, 2023, identifying studies investigating SC-EVs therapy in AD rodent models. Outcome measures included Morris water maze and Y maze tests, β-amyloid pathology, and inflammatory markers. Statistical analyses utilized Stata 15.1 and R software. RESULTS This meta-analysis of 16 studies (2017-2023, 314 animals) demonstrates significant efficacy of SC-EVs therapy in AD models. Pooled analyses demonstrated that SC-EVs therapy significantly increased the learning function as measured by Morris water maze tests (MWM) by -1.83 (95% CI = -2.51 to -1.15, p < 0.0001), Y maze test by 1.66 (95% CI = 1.03 to 2.28, p < 0.0001), decreased Aβ plaques in the hippocampal by -2.10 (95% CI = -2.96 to -1.23, p < 0.0001), and proinflammatory cytokines Tumor necrosis factor alpha (TNFα) by -2.61 (95% CI = -4.87 to -0.35, p < 0.05), Interleukin-1 beta (IL-1β) by -2.37 (95% CI = -3.68 to -1.05, p < 0.001). CONCLUSIONS SC-EVs therapy shows promise in enhancing cognitive function and mitigating AD progression in preclinical models. Future research should focus on standardizing methodologies and comparing SC-EVs isolation techniques and dosing strategies to facilitate clinical translation.
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Affiliation(s)
- Huiyin Deng
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Jing Zhao
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Jiuyi Li
- Department of Anesthesiology, the Fouth People's Hospital of Changsha, 410006 Changsha, Hunan, China
| | - Chunli Chen
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Xiaomei Wu
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Lite Ge
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, 410003 Changsha, Hunan, China
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Shah S, Mansour HM, Aguilar TM, Lucke-Wold B. Mesenchymal Stem Cell-Derived Exosomes as a Neuroregeneration Treatment for Alzheimer's Disease. Biomedicines 2024; 12:2113. [PMID: 39335626 PMCID: PMC11428860 DOI: 10.3390/biomedicines12092113] [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: 08/04/2024] [Revised: 09/12/2024] [Accepted: 09/15/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is the most prevalent kind of dementia and is a long-term degenerative disease. Pathologically, it is defined by the development of extracellular amyloid-β plaques and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein. This causes neuronal death, particularly in the hippocampus and cortex. Mesenchymal stem cell (MSC)-derived exosomes have been identified as possibly therapeutic and have promise for Alzheimer's disease due to their regenerative characteristics. METHODS A systematic retrieval of information was performed on PubMed. A total of 60 articles were found in a search on mesenchymal stem cells, exosomes, and Alzheimer's disease. A total of 16 ongoing clinical trials were searched and added from clinicaltrials.gov. We added 23 supporting articles to help provide information for certain sections. In total, we included 99 articles in this manuscript: 50 are review articles, 13 are preclinical studies, 16 are clinical studies, 16 are ongoing clinical trials, and 4 are observational studies. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on mesenchymal stem cell exosomes for Alzheimer's disease were searched on clinicaltrials.gov. RESULTS Several experimental investigations have shown that MSC-Exo improves cognitive impairment in rats. In this review paper, we summarized existing understanding regarding the molecular and cellular pathways behind MSC-Exo-based cognitive function restoration, with a focus on MSC-Exo's therapeutic potential in the treatment of Alzheimer's disease. CONCLUSION AD is a significant health issue in our culture and is linked to several important neuropathological characteristics. Exosomes generated from stem cells, such as mesenchymal stem cells (MSCs) or neural stem cells (NSCs), have been examined more and more in a variety of AD models, indicating that they may be viable therapeutic agents for the treatment of diverse disorders. Exosome yields may be increased, and their therapeutic efficacy can be improved using a range of tailored techniques and culture conditions. It is necessary to provide standardized guidelines for exosome manufacture to carry out excellent preclinical and clinical research.
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Affiliation(s)
- Siddharth Shah
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA (B.L.-W.)
| | - Hadeel M. Mansour
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA (B.L.-W.)
| | - Tania M. Aguilar
- College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA (B.L.-W.)
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50
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Shekho D, Mishra R, Kamal R, Bhatia R, Awasthi A. Breaking Barriers in Alzheimer's Disease: the Role of Advanced Drug Delivery Systems. AAPS PharmSciTech 2024; 25:207. [PMID: 39237748 DOI: 10.1208/s12249-024-02923-6] [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: 04/17/2024] [Accepted: 08/18/2024] [Indexed: 09/07/2024] Open
Abstract
Alzheimer's disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-β (Aβ) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations.
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Affiliation(s)
- Devank Shekho
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Ritika Mishra
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Raj Kamal
- Department of Quality Assurance, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Rohit Bhatia
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ankit Awasthi
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India.
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
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