1
|
Goyal A, Afzal M, Goyal K, Ganesan S, Kumari M, Sunitha S, Dash A, Saini S, Rana M, Gupta G, Ali H, Wong LS, Kumarasamy V, Subramaniyan V. MSC-derived extracellular vesicles: Precision miRNA delivery for overcoming cancer therapy resistance. Regen Ther 2025; 29:303-318. [PMID: 40237010 PMCID: PMC11999318 DOI: 10.1016/j.reth.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/04/2025] [Accepted: 03/18/2025] [Indexed: 04/17/2025] Open
Abstract
Cancer remains a prominent worldwide health concern, presenting existing therapies with frequent difficulties, including major toxicity, limited effectiveness, and treatment resistance emergence. These issues highlight the necessity for novel and enhanced remedies. Exosomes, tiny extracellular vesicles that facilitate intercellular communication, have attracted interest for their potential medicinal applications. Carrying a variety of molecules, including microRNAs, small interfering RNAs, long non-coding RNAs, proteins, lipids, and DNA, these vesicles are positioned as promising cancer treatment options. Current studies have increasingly investigated the capacity of microRNAs as a strategic approach for combating malignancy. Mesenchymal stem cells (MSC) are recognized for their aptitude to augment blood vessel formation, safeguard against cellular death, and modulate immune responses. Consequently, researchers examine exosomes derived from MSCs as a safer, non-cellular choice over therapies employing MSCs, which risk undesirable differentiation. The focus is shifting towards employing miRNA-encapsulated exosomes sourced from MSCs to target and heal cancerous cells selectively. However, the exact functions of miRNAs within MSC-derived exosomes in the context of cancer are still not fully understood. Additional exploration is necessary to clarify the role of these miRNAs in malignancy progression and to pinpoint viable therapeutic targets. This review offers a comprehensive examination of exosomes derived from mesenchymal stem cells, focusing on the encapsulation of miRNAs, methods for enhancing cellular uptake and stability, and their potential applications in cancer treatment. It also addresses the difficulties linked to this methodology and considers future avenues, including insights from current clinical oncology research.
Collapse
Affiliation(s)
- Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - S. Sunitha
- Department of CHEMISTRY, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Aniruddh Dash
- Department of Orthopaedics IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751030, India
| | - Suman Saini
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
| |
Collapse
|
2
|
Jin P, Bai X. Exploring the roles and clinical potential of exosome-derived non-coding RNAs in glioma. IBRO Neurosci Rep 2025; 18:323-337. [PMID: 40034544 PMCID: PMC11872630 DOI: 10.1016/j.ibneur.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 01/17/2025] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Non-coding accounts for 98 %-99 % of the human genome and performs many essential regulatory functions in eukaryotes, involved in cancer development and development. Non-coding RNAs are abundantly enriched in exosomes, which play a biological role as vectors. Some biofunctional non-coding RNAs are specifically designed as exosomes for the treatment of cancers such as glioma. Glioma is one of the most common primary tumors within the skull and has varying degrees of malignancy and histologic subtypes of grades I-IV. Gliomas are characterized by high malignancy and an abundant blood supply due to rapid cell proliferation and vascularization, often with a poor prognosis. Exosomal non-coding RNAs can be involved in the tumorigenesis process of glioma from multiple directions, such as angiogenesis, tumor proliferation, metastatic invasion, immune evasion, apoptosis, and autophagy. Therefore, non-coding RNAs in exosomes are suitable as markers or therapeutic targets for early diagnosis of diseases and for predicting the prognosis of a variety of diseases. Regulating exosome production and the level of exosomal non-coding RNA expression may be a new approach to prevent or eliminate glioma. In this review, we review the origin and characteristics of exosomal non-coding RNAs, and introduce the functional studies of exosomal non-coding RNAs in glioma and their potential clinical applications, in order to broaden new ideas for the treatment of glioma.
Collapse
Affiliation(s)
- Peng Jin
- Department of Neurosurgery, Hulunbuir People’s Hospital, Hulunbuir, Inner Mongolia Autonomous Region 021000, China
| | - Xue Bai
- Department of Intensive Care Unit, Hulunbuir People’s Hospital, No. 20, Shengli Street, Hailar District, Hulunbuir, Inner Mongolia Autonomous Region 021000, China
| |
Collapse
|
3
|
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.
Collapse
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.
| |
Collapse
|
4
|
Ramezani A, Rahnama M, Mahmoudian F, Shirazi F, Ganji M, Bakhshi S, Khalesi B, Hashemi ZS, Khalili S. Current Understanding of the Exosomes and Their Associated Biomolecules in the Glioblastoma Biology, Clinical Treatment, and Diagnosis. J Neuroimmune Pharmacol 2025; 20:48. [PMID: 40299204 DOI: 10.1007/s11481-025-10204-7] [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: 07/23/2024] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
Glioblastoma is the most common and aggressive brain tumor with a low survival rate. Due to its heterogeneous composition, high invasiveness, and frequent recurrence after surgery, treatment success has been limited. In addition, due to the brain's unique immune status and the suppressor tumor microenvironment (TME), glioblastoma treatment has faced more challenges. Exosomes play a critical role in cancer metastasis by regulating cell-cell interactions that promote tumor growth, angiogenesis, metastasis, treatment resistance, and immunological regulation in the tumor microenvironment. This review explores the pivotal role of exosomes in the development of glioblastoma, with a focus on their potential as non-invasive biomarkers for prognosis, early detection and real-time monitoring of disease progression. Notably, exosome-based drug delivery methods hold promise for overcoming the blood-brain barrier (BBB) and developing targeted therapies for glioblastoma. Despite challenges in clinical translation, the potential for personalized exosome = -054321`therapies and the capacity to enhance therapeutic responses in glioblastoma, present intriguing opportunities for improving patient outcomes. It seems that getting a good and current grasp of the role of exosomes in the fight against glioblastoma would properly serve the scientific community to further their understanding of the related potentials of these biological moieties.
Collapse
Affiliation(s)
- Aghdas Ramezani
- Department of Molecular Imaging, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Maryam Rahnama
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Mahmoudian
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Shirazi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Mahmoud Ganji
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Shohreh Bakhshi
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Education and Extension Organization, Razi Vaccine and Serum Research Institute, Agricultural Research, Karaj, 3197619751, Iran
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran.
| |
Collapse
|
5
|
Tiwari PK, Chaudhary AA, Gupta S, Chouhan M, Singh HN, Rustagi S, Khan SUD, Kumar S. Extracellular vesicles in triple-negative breast cancer: current updates, challenges and future prospects. Front Mol Biosci 2025; 12:1561464. [PMID: 40297849 PMCID: PMC12034555 DOI: 10.3389/fmolb.2025.1561464] [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: 01/15/2025] [Accepted: 02/25/2025] [Indexed: 04/30/2025] Open
Abstract
Breast cancer (BC) remains a complex and widespread problem, affecting millions of women worldwide, Among the various subtypes of BC, triple-negative breast cancer (TNBC) is particularly challenging, representing approximately 20% of all BC cases, and the survival rate of TNBC patients is generally worse than other subtypes of BC. TNBC is a heterogeneous disease characterized by lack of expression of three receptors: estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2), resulting conventional hormonal therapies are ineffective for its management. Despite various therapeutic approaches have been explored, but no definitive solution has been found yet for TNBC. Current treatments options are chemotherapy, immunotherapy, radiotherapy and surgery, although, these therapies have some limitations, such as the development of resistance to anti-cancer drugs, and off-target toxicity, which remain primary obstacles and significant challenges for TNBC. Several findings have shown that EVs exhibit significant therapeutic promise in many diseases, and a similar important role has been observed in various types of tumor. Studies suggest that EVs may offer a potential solution for the management of TNBC. This review highlights the multifaceted roles of EVs in TNBC, emphasizing their involvement in disease progression, diagnosis and therapeutic approach, as well as their potential as biomarkers and drug delivery.
Collapse
Affiliation(s)
- Prashant Kumar Tiwari
- Biological and Bio-Computational Lab, Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India
| | - Mandeep Chouhan
- Biological and Bio-Computational Lab, Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Himanshu Narayan Singh
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, United States
| | - Sarvesh Rustagi
- Department of Food Technology, School of Applied and Life science, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Salah-Ud-Din Khan
- Department of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Sanjay Kumar
- Biological and Bio-Computational Lab, Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| |
Collapse
|
6
|
Kaçaroğlu D, Yaylacı S, Ulaşlı AM. Dual facets of MSC-derived small EVs: regulatory insights into antitumor mechanisms in pancreatic ductal adenocarcinoma. Med Oncol 2025; 42:158. [PMID: 40208413 PMCID: PMC11985665 DOI: 10.1007/s12032-025-02713-5] [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: 01/14/2025] [Accepted: 03/30/2025] [Indexed: 04/11/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, fibrotic, immunosuppressive, and desmoplastic extracellular matrix. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have emerged as a novel therapeutic strategy. Nonetheless, the potential dual effects of MSC-EVs on tumor cells warrant careful consideration. This study aimed to evaluate the mechanistic effects of MSC-EVs on PDAC. Wharton's Jelly (WJ) MSC-derived small EVs were isolated using ultracentrifugation method and analyzed through nanoparticle tracking analysis (NTA) and flow cytometry. EVs were added to Panc-1 cells at concentrations of 4000-10,000 EVs per cell, and a preliminary MTT assay was performed. In subsequent experiments, EVs were added to Panc-1 cells at concentrations of only 4000, 8000 and 12,000 EVs per cell. After 24 h, apoptosis and cell cycle analyses were performed. The expression of epithelial-mesenchymal transition (EMT)-related and immune-related genes was analyzed. Cell cycle analysis showed higher G1 phase percentage in the control group (31%) compared to MSC EV-treated groups (35-36%). Apoptosis analysis revealed similar viable and necrotic cell percentages among the control (80% viable) and treated groups (approximately 78-79% viable). The CD44, VIM, MMP9, TIMP1, and ZEB1 genes were downregulated in treated groups compared to the control. Although CLDN1 and CDH1 genes were upregulated at the lowest EV concentration, they were downregulated at higher EV concentrations. Immune gene analysis showed downregulation of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-1α, IL-1β) and upregulation of the anti-inflammatory cytokine IL-10 in treated groups. This study revealed the dual role of WJ-MSC small EVs in PDAC. While they suppressed cell proliferation and modulated EMT markers, indicating their antitumor potential, they also exhibited an immunosuppressive profile. These findings highlight both the promise and challenges of using WJ-MSC small EVs as therapeutic agents, necessitating further studies to optimize their application and balance their effects.
Collapse
Affiliation(s)
- Demet Kaçaroğlu
- Faculty of Medicine, Department of Medical Biology, Lokman Hekim University, Söğütözü, 2179. Sk. No:6, 06530, Çankaya, Ankara, Turkey.
| | - Seher Yaylacı
- Faculty of Medicine, Department of Medical Biology, Lokman Hekim University, Söğütözü, 2179. Sk. No:6, 06530, Çankaya, Ankara, Turkey
| | - Alper Murat Ulaşlı
- Stem Cell Institute, Interdisciplinary Stem Cell and Regenerative Medicine Department, Ankara University, Cevizlidere, Ceyhun Atuf Kansu Cd. No:169, 06520, Çankaya, Ankara, Turkey
| |
Collapse
|
7
|
Araujo-Abad S, Berna JM, Lloret-Lopez E, López-Cortés A, Saceda M, de Juan Romero C. Exosomes: from basic research to clinical diagnostic and therapeutic applications in cancer. Cell Oncol (Dordr) 2025; 48:269-293. [PMID: 39298081 PMCID: PMC11997007 DOI: 10.1007/s13402-024-00990-2] [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: 08/30/2024] [Indexed: 09/21/2024] Open
Abstract
Cancer continues to pose a global threat despite potent anticancer drugs, often accompanied by undesired side effects. To enhance patient outcomes, sophisticated multifunctional approaches are imperative. Small extracellular vesicles (EVs), a diverse family of naturally occurring vesicles derived from cells, offer advantages over synthetic carriers. Among the EVs, the exosomes are facilitating intercellular communication with minimal toxicity, high biocompatibility, and low immunogenicity. Their tissue-specific targeting ability, mediated by surface molecules, enables precise transport of biomolecules to cancer cells. Here, we explore the potential of exosomes as innovative therapeutic agents, including cancer vaccines, and their clinical relevance as biomarkers for clinical diagnosis. We highlight the cargo possibilities, including nucleic acids and drugs, which make them a good delivery system for targeted cancer treatment and contrast agents for disease monitoring. Other general aspects, sources, and the methodology associated with therapeutic cancer applications are also reviewed. Additionally, the challenges associated with translating exosome-based therapies into clinical practice are discussed, together with the future prospects for this innovative approach.
Collapse
Affiliation(s)
- Salomé Araujo-Abad
- Cancer Research Group, Faculty of Engineering and Applied Sciences, Universidad de Las Américas, Quito, 170124, Ecuador
| | - José Marcos Berna
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain
| | - Elena Lloret-Lopez
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, 170124, Ecuador
| | - Miguel Saceda
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain
| | - Camino de Juan Romero
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, Alicante, 03203, Spain.
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda. Universidad s/n, Ed. Torregaitán, Elche, Alicante, 03202, Spain.
| |
Collapse
|
8
|
Zhang X, Artz N, Steindler DA, Hingtgen S, Satterlee AB. Exosomes: Traversing the blood-brain barrier and their therapeutic potential in brain cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189300. [PMID: 40097050 DOI: 10.1016/j.bbcan.2025.189300] [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: 10/01/2024] [Revised: 03/07/2025] [Accepted: 03/09/2025] [Indexed: 03/19/2025]
Abstract
The blood-brain barrier (BBB) presents a major challenge for the effective delivery of therapeutic agents to the brain tumor cells from the peripheral blood circulation, making the treatment of central nervous system (CNS)-related cancers more difficult and resistant to both standard treatments and emerging therapies. Exosomes, which serve as messengers for intercellular communication throughout the body, can naturally or be modified to penetrate the BBB. Recently, exosomes have been increasingly explored as an invasive or non-invasive approach for delivering therapeutic agents to the CNS. With their low immunogenicity, ease of modification, excellent cargo protection, and inherent ability to cross the BBB, exosomes hold great promise for revolutionizing targeted therapy for CNS-related diseases, including brain cancer. In this review, we highlight recent discoveries and insights into the mechanisms exosomes use to penetrate the BBB, the methods they employ to payload diverse therapeutics, and their roles in transporting therapeutic compounds for brain cancer and other neurological disorders.
Collapse
Affiliation(s)
- Xiaopei Zhang
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Nichole Artz
- Department of Pediatric Hematology/Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Dennis A Steindler
- Steindler Consulting, Boston, MA, USA; Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Andrew Benson Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| |
Collapse
|
9
|
Balaraman AK, Arockia Babu M, Afzal M, Sanghvi G, M M R, Gupta S, Rana M, Ali H, Goyal K, Subramaniyan V, Wong LS, Kumarasamy V. Exosome-based miRNA delivery: Transforming cancer treatment with mesenchymal stem cells. Regen Ther 2025; 28:558-572. [PMID: 40034540 PMCID: PMC11872554 DOI: 10.1016/j.reth.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/14/2025] [Accepted: 01/25/2025] [Indexed: 03/05/2025] Open
Abstract
Recently, increasing interest has been in utilizing mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), especially exosomes, as nanocarriers for miRNA delivery in cancer treatment. Due to such characteristics, nanocarriers are specific: biocompatible, low immunogenicity, and capable of spontaneous tumor accumulation. MSC-EVs were loaded with therapeutic miRNAs and minimized their susceptibility to degradation by protecting the miRNA from accessibility to degrading enzymes and providing targeted delivery of the miRNAs to the tumor cells to modulate oncogenic pathways. In vitro and in vivo experiments suggest that MSC-EVs loaded with miRNAs may inhibit tumor growth, prevent metastasis, and increase the effectiveness of chemotherapy and radiotherapy. However, these improvements present difficulties such as isolation, scalability, and stability of delivered miRNA during storage. Furthermore, the issues related to off-target effects, as well as immunogenicity, can be a focus. The mechanisms of miRNA loading into MSC-EVs, as well as their targeting efficiency and therapeutic potential, can be outlined in this manuscript. For the final part of the manuscript, the current advances in MSC-EV engineering and potential strategies for clinical application have been described. The findings of MSC-EVs imply that they present MSC-EVs as a second-generation tool for precise oncology.
Collapse
Affiliation(s)
- Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya, Selangor, 63000, Malaysia
| | - M. Arockia Babu
- Institute of Pharmaceutical Research, GLA UNIVERSITY, Mathura, UP, 281406, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Sofia Gupta
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Vetriselvan Subramaniyan
- Division of Pharmacology, School of Medical and Life Sciences, Sunway University Jalan Universiti, Bandar Sunway, 47500 Selangor Darul Ehsan, Malaysia
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology, Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
| |
Collapse
|
10
|
Ding HY, Zhou H, Jiang Y, Chen SS, Wu XX, Li Y, Luo J, Zhang PF, Ding YN. Lipid Nanovesicles in Cancer Treatment: Improving Targeting and Stability of Antisense Oligonucleotides. Drug Des Devel Ther 2025; 19:1001-1023. [PMID: 39967902 PMCID: PMC11834698 DOI: 10.2147/dddt.s507402] [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: 11/19/2024] [Accepted: 02/04/2025] [Indexed: 02/20/2025] Open
Abstract
Cancer remains a leading cause of mortality worldwide, accounting for approximately 10 million deaths annually. Standard treatments, including surgery, radiotherapy, and chemotherapy, often result in damage to healthy cells and severe toxic side effects. In recent years, antisense technology therapeutics, which interfere with RNA translation through complementary base pairing, have emerged as promising approaches for cancer treatment. Despite the availability of various antisense oligonucleotide (ASO) drugs on the market, challenges such as poor active targeting and susceptibility to clearance by circulating enzymes remain. Compared with other delivery systems, lipid nanovesicle (LNV) delivery systems offer a potential solution that uniquely enhances ASO targeting and stability. Studies have shown that LNVs can increase the accumulation of ASOs in tumor sites several-fold, significantly reducing systemic toxic reactions and demonstrating increased therapeutic efficiency in preclinical models. Additionally, LNVs can protect ASOs from enzymatic degradation within the body, extending their half-life and thus enhancing their therapeutic effects. This paper provides a comprehensive review of recent examples and applications of LNV delivery of ASOs in cancer treatment, highlighting their unique functions and outcomes. Furthermore, this paper discusses the key challenges and potential impacts of this innovative approach to cancer therapy.
Collapse
Affiliation(s)
- Hui-yan Ding
- Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang, 310022, People’s Republic of China
- Zhejiang Provincial Research Center for Innovative Technology and Equipment in Interventional Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, 999078, People’s Republic of China
| | - Han Zhou
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
| | - Yi Jiang
- Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang, 310022, People’s Republic of China
- Zhejiang Provincial Research Center for Innovative Technology and Equipment in Interventional Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
| | - Si-si Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People’s Republic of China
| | - Xiao-xia Wu
- Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang, 310022, People’s Republic of China
- Zhejiang Provincial Research Center for Innovative Technology and Equipment in Interventional Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
| | - Yang Li
- Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang, 310022, People’s Republic of China
- Zhejiang Provincial Research Center for Innovative Technology and Equipment in Interventional Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
| | - Jun Luo
- Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang, 310022, People’s Republic of China
- Zhejiang Provincial Research Center for Innovative Technology and Equipment in Interventional Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
| | - Peng-fei Zhang
- Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, 010020, People’s Republic of China
| | - Yi-nan Ding
- Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang, 310022, People’s Republic of China
- Zhejiang Provincial Research Center for Innovative Technology and Equipment in Interventional Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, People’s Republic of China
| |
Collapse
|
11
|
Baran Z, Çetinkaya M, Baran Y. Mesenchymal Stem Cells in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:149-177. [PMID: 39470980 DOI: 10.1007/5584_2024_824] [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: 11/01/2024]
Abstract
The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies.
Collapse
Affiliation(s)
- Züleyha Baran
- Laboratory of Molecular Pharmacology, Department of Pharmacology, Anadolu University, Eskişehir, Turkey
| | - Melisa Çetinkaya
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey
| | - Yusuf Baran
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
| |
Collapse
|
12
|
Zheng L, Chang R, Liang B, Wang Y, Zhu Y, Jia Z, Fan J, Zhang Z, Du B, Kong D. Overcoming drug resistance through extracellular vesicle-based drug delivery system in cancer treatment. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:50. [PMID: 39802949 PMCID: PMC11724354 DOI: 10.20517/cdr.2024.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 11/15/2024] [Accepted: 12/03/2024] [Indexed: 01/16/2025]
Abstract
Drug resistance is a major challenge in cancer therapy that often leads to treatment failure and disease relapse. Despite advancements in chemotherapeutic agents and targeted therapies, cancers often develop drug resistance, making these treatments ineffective. Extracellular vesicles (EVs) have gained attention for their potential applications in drug delivery because of their natural origin, biocompatibility, and ability to cross biological barriers. Using the unique properties of EVs could enhance drug accumulation at target sites, minimize systemic toxicity, and precisely target specific cells. Here, we discuss the characteristics and functionalization of EVs, the mechanisms of drug resistance, and the applications of engineered EVs to overcome drug resistance. This review provides a comprehensive overview of the advancements in EV-based drug delivery systems and their applications in overcoming cancer drug resistance. We highlight the potential of EV-based drug delivery systems to revolutionize cancer therapy and offer promising strategies for more effective treatment modalities.
Collapse
Affiliation(s)
- Long Zheng
- College of Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
- Authors contributed equally
| | - Ruibai Chang
- College of Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
- Authors contributed equally
| | - Bingjing Liang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
- Authors contributed equally
| | - Yitong Wang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Yushan Zhu
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Zijing Jia
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Jindian Fan
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Zhe Zhang
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| | - Bo Du
- Tianjin Key Laboratory of Biomedical Materials, Biomedical Barriers Research Center, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Dexin Kong
- Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences; Tianjin Medical University, Tianjin 300070, China
- Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China
| |
Collapse
|
13
|
Molavand M, Ebrahimnezhade N, Kiani A, Yousefi B, Nazari A, Majidinia M. Regulation of autophagy by non-coding RNAs in human glioblastoma. Med Oncol 2024; 41:260. [PMID: 39375229 DOI: 10.1007/s12032-024-02513-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 09/18/2024] [Indexed: 10/09/2024]
Abstract
Glioblastoma, a lethal form of brain cancer, poses substantial challenges in treatment due to its aggressive nature and resistance to standard therapies like radiation and chemotherapy. Autophagy has a crucial role in glioblastoma progression by supporting cellular homeostasis and promoting survival under stressful conditions. Non-coding RNAs (ncRNAs) play diverse biological roles including, gene regulation, chromatin remodeling, and the maintenance of cellular homeostasis. Emerging evidence reveals the intricate regulatory mechanisms of autophagy orchestrated by non-coding RNAs (ncRNAs) in glioblastoma. The diverse roles of these ncRNAs in regulating crucial autophagy-related pathways, including AMPK/mTOR signaling, the PI3K/AKT pathway, Beclin1, and other autophagy-triggering system regulation, sheds light on ncRNAs biological mechanisms in the proliferation, invasion, and therapy response of glioblastoma cells. Furthermore, the clinical implications of targeting ncRNA-regulated autophagy as a promising therapeutic strategy for glioblastoma treatment are in the spotlight of ongoing studies. In this review, we delve into our current understanding of how ncRNAs regulate autophagy in glioblastoma, with a specific focus on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), and their intricate interplay with therapy response.
Collapse
Affiliation(s)
- Mehran Molavand
- Student Research Commitee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Ebrahimnezhade
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Arash Kiani
- Student Research Commite, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran.
- Molecular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ahmad Nazari
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran.
- Tehran University of Medical Sciences, Tehran, Iran.
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| |
Collapse
|
14
|
Convento MB, de Oliveira AS, Boim MA, Borges FT. Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles as Natural Nanocarriers in the Treatment of Nephrotoxic Injury In Vitro. Cells 2024; 13:1658. [PMID: 39404421 PMCID: PMC11475496 DOI: 10.3390/cells13191658] [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: 08/10/2024] [Revised: 10/03/2024] [Accepted: 10/05/2024] [Indexed: 10/19/2024] Open
Abstract
Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-EVs) are valuable in nanomedicine as natural nanocarriers, carrying information molecules from their parent cells and fusing with targeted cells. miRNA-126, specific to endothelial cells and derived from these vesicles, supports vascular integrity and angiogenesis and has protective effects in kidney diseases. OBJECTIVE This study investigates the delivery of miRNA-126 and anti-miRNA-126 via UC-EVs as natural nanocarriers for treating nephrotoxic injury in vitro. METHOD The umbilical cord-derived mesenchymal stem cell and UC-EVs were characterized according to specific guidelines. Rat kidney proximal tubular epithelial cells (tubular cells) were exposed to nephrotoxic injury through of gentamicin and simultaneously treated with UC-EVs carrying miRNA-126 or anti-miRNA-126. Specific molecules that manage cell cycle progression, proliferation cell assays, and newly synthesized DNA and DNA damage markers were evaluated. RESULTS We observed significant increases in the expression of cell cycle markers, including PCNA, p53, and p21, indicating a positive cell cycle regulation with newly synthesized DNA via BrDU. The treatments reduced the expression of DNA damage marker, such as H2Ax, suggesting a lower rate of cellular damage. CONCLUSIONS The UC-EVs, acting as natural nanocarriers of miRNA-126 and anti-miRNA-126, offer nephroprotective effects in vitro. Additionally, other components in UC-EVs, such as proteins, lipids, and various RNAs, might also contribute to these effects.
Collapse
Affiliation(s)
- Márcia Bastos Convento
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04038-901, Brazil; (A.S.d.O.) (M.A.B.); (F.T.B.)
| | - Andreia Silva de Oliveira
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04038-901, Brazil; (A.S.d.O.) (M.A.B.); (F.T.B.)
| | - Mirian Aparecida Boim
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04038-901, Brazil; (A.S.d.O.) (M.A.B.); (F.T.B.)
| | - Fernanda Teixeira Borges
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04038-901, Brazil; (A.S.d.O.) (M.A.B.); (F.T.B.)
- Interdisciplinary Postgraduate Program in Health Sciences, Cruzeiro do Sul University, Sao Paulo 01506-000, Brazil
| |
Collapse
|
15
|
Cunha Silva L, Branco F, Cunha J, Vitorino C, Gomes C, Carrascal MA, Falcão A, Miguel Neves B, Teresa Cruz M. The potential of exosomes as a new therapeutic strategy for glioblastoma. Eur J Pharm Biopharm 2024; 203:114460. [PMID: 39218361 DOI: 10.1016/j.ejpb.2024.114460] [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: 10/03/2023] [Revised: 07/30/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024]
Abstract
Glioblastoma (GBM) stands for the most common and aggressive type of brain tumour in adults. It is highly invasive, which explains its short rate of survival. Little is known about its risk factors, and current therapy is still ineffective. Hence, efforts are underway to develop novel and effective treatment approaches against this type of cancer. Exosomes are being explored as a promising strategy for conveying and delivering therapeutic cargo to GBM cells. They can fuse with the GBM cell membrane and, consequently, serve as delivery systems in this context. Due to their nanoscale size, exosomes can cross the blood-brain barrier (BBB), which constitutes a significant hurdle to most chemotherapeutic drugs used against GBM. They can subsequently inhibit oncogenes, activate tumour suppressor genes, induce immune responses, and control cell growth. However, despite representing a promising tool for the treatment of GBM, further research and clinical studies regarding exosome biology, engineering, and clinical applications still need to be completed. Here, we sought to review the application of exosomes in the treatment of GBM through an in-depth analysis of the scientific and clinical studies on the entire process, from the isolation and purification of exosomes to their design and transformation into anti-oncogenic drug delivery systems. Surface modification of exosomes to enhance BBB penetration and GBM-cell targeting is also a topic of discussion.
Collapse
Affiliation(s)
- Leonor Cunha Silva
- Faculty of Pharmacy, FFUC, University of Coimbra, Coimbra 3000-548, Portugal
| | - Francisco Branco
- Faculty of Pharmacy, FFUC, University of Coimbra, Coimbra 3000-548, Portugal
| | - Joana Cunha
- Faculty of Pharmacy, FFUC, University of Coimbra, Coimbra 3000-548, Portugal
| | - Carla Vitorino
- Faculty of Pharmacy, FFUC, University of Coimbra, Coimbra 3000-548, Portugal; Coimbra Chemistry Centre, Institute of Molecular Sciences - IMS, Department of Chemistry, University of Coimbra, Coimbra 3004 535, Portugal
| | - Célia Gomes
- Coimbra Institute for Clinical and Biomedical Research, iCBR, Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal; Center for Innovation in Biomedicine and Biotechnology, CIBB, University of Coimbra, Coimbra 3000-504, Portugal
| | - Mylène A Carrascal
- Tecnimede Group, Sintra 2710-089, Portugal; Center for Neuroscience and Cell Biology, CNC, University of Coimbra, Coimbra 3004-504, Portugal
| | - Amílcar Falcão
- Faculty of Pharmacy, FFUC, University of Coimbra, Coimbra 3000-548, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research, CIBIT, University of Coimbra, Coimbra 3000-548, Portugal
| | - Bruno Miguel Neves
- Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro 3810-193, Portugal
| | - Maria Teresa Cruz
- Faculty of Pharmacy, FFUC, University of Coimbra, Coimbra 3000-548, Portugal; Coimbra Institute for Clinical and Biomedical Research, iCBR, Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal; Center for Neuroscience and Cell Biology, CNC, University of Coimbra, Coimbra 3004-504, Portugal.
| |
Collapse
|
16
|
Yang L, Niu Z, Ma Z, Wu X, Vong CT, Li G, Feng Y. Exploring the clinical implications and applications of exosomal miRNAs in gliomas: a comprehensive study. Cancer Cell Int 2024; 24:323. [PMID: 39334350 PMCID: PMC11437892 DOI: 10.1186/s12935-024-03507-x] [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: 05/11/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Gliomas are aggressive brain tumors associated with poor prognosis and limited treatment options due to their invasive nature and resistance to current therapeutic modalities. Research suggests that exosomal microRNAs have emerged as key players in intercellular communication within the tumor microenvironment, influencing tumor progression and therapeutic responses. Exosomal microRNAs (miRNAs), small non-coding RNAs, are crucial in glioma development, invasion, metastasis, angiogenesis, and immune evasion by binding to target genes. This comprehensive review examines the clinical relevance and implications of exosomal miRNAs in gliomas, highlighting their potential as diagnostic biomarkers, therapeutic targets and prognosis biomarker. Additionally, we also discuss the limitations of current exsomal miRNA treatments and address challenges and propose future directions for leveraging exosomal miRNAs in precision oncology for glioma management.
Collapse
Affiliation(s)
- Liang Yang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Zhen Niu
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Zhixuan Ma
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Xiaojie Wu
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Chi Teng Vong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macau, China
| | - Ge Li
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510100, China.
| | - Ying Feng
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
| |
Collapse
|
17
|
Li Y, Wang Y, Zhang Y, Zhu Y, Dong Y, Cheng H, Zhang Y, Wang Y, Li Z, Gao J. Engineered mesenchymal stem cell-derived extracellular vesicles: kill tumors and protect organs. Theranostics 2024; 14:6202-6217. [PMID: 39431009 PMCID: PMC11488101 DOI: 10.7150/thno.99618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 08/20/2024] [Indexed: 10/22/2024] Open
Abstract
Solid tumors cause 90% of cancers and remain the primary cause of mortality. However, treating solid tumors presents significant challenges due to the complex tumor microenvironment and drug resistance, leading to inadequate treatment targeting and severe side effects. Surgery, radiotherapy, and chemotherapy Although it is an effective method for the treatment of solid tumors, it can lead to organ dysfunction and affect patient prognosis. Therefore, it is imperative to improve treatment precision and organ repair capabilities to manage solid tumors. Mesenchymal stem cell extracellular vesicles (MSC-EVs) have wide application prospects as a new agent for solid tumor therapy. Firstly, MSC-EVs is a derivative of MSCs. It has the function of promoting tissue regeneration by inducing dedifferentiation in surviving cells after injury. Additionally, MSC-EVs offer unique advantages in terms of safety, stability and penetrability, making them a promising extracellular therapeutic modality for solid tumor treatment. Finally, MSC-EVs are able to enhance therapeutic efficacy through engineering strategies. To sum up, this review takes MSC-EVs as its object. And then we discuss recent advancements and engineering strategies in the use of MSC-EVs for soid tumor suppression. This review aims to inspire researchers to devise a new method for effectively treat solid tumors.
Collapse
Affiliation(s)
- Yu Li
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- Stem Cell and Regeneration Medicine Institute, Research Center of Translational Medicine, Naval Medical University, Shanghai, 200433, China
- Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yao Wang
- Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- College of Life Science, Mudanjiang Medical University, Heilongjiang Mudanjiang, 157011, China
| | - Yu Zhang
- Shanghai Key Laboratory of Cell Engineering, Shanghai, 200120, China
| | - Yuruchen Zhu
- School of Basic Medical Sciences, Naval Medical University, Shanghai, 200433, China
| | - Yuhui Dong
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Haobin Cheng
- School of Basic Medical Sciences, Naval Medical University, Shanghai, 200433, China
| | - Yinan Zhang
- School of Chemical Science and Engineering, Tongji University, Shanghai, 200092, China
| | - Yue Wang
- Stem Cell and Regeneration Medicine Institute, Research Center of Translational Medicine, Naval Medical University, Shanghai, 200433, China
- Shanghai Key Laboratory of Cell Engineering, Shanghai, 200120, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- National Clinical Research Center for Digestive Diseases, Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- National Key Laboratory of lmmunology and Inflammation, Naval Medical University, Shanghai, 200433, China
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai, 200433, China
| | - Jie Gao
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- Changhai Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Shanghai, 200433, China
| |
Collapse
|
18
|
Rasouli A, Roshangar L, Hosseini M, Pourmohammadfazel A, Nikzad S. Beyond boundaries: The therapeutic potential of exosomes in neural microenvironments in neurological disorders. Neuroscience 2024; 553:98-109. [PMID: 38964450 DOI: 10.1016/j.neuroscience.2024.06.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/18/2024] [Accepted: 06/25/2024] [Indexed: 07/06/2024]
Abstract
Neurological disorders are a diverse group of conditions that can significantly impact individuals' quality of life. The maintenance of neural microenvironment homeostasis is essential for optimal physiological cellular processes. Perturbations in this delicate balance underlie various pathological manifestations observed across various neurological disorders. Current treatments for neurological disorders face substantial challenges, primarily due to the formidable blood-brain barrier and the intricate nature of neural tissue structures. These obstacles have resulted in a paucity of effective therapies and inefficiencies in patient care. Exosomes, nanoscale vesicles that contain a complex repertoire of biomolecules, are identifiable in various bodily fluids. They hold substantial promise in numerous therapeutic interventions due to their unique attributes, including targeted drug delivery mechanisms and the ability to cross the BBB, thereby enhancing their therapeutic potential. In this review, we investigate the therapeutic potential of exosomes across a range of neurological disorders, including neurodegenerative disorders, traumatic brain injury, peripheral nerve injury, brain tumors, and stroke. Through both in vitro and in vivo studies, our findings underscore the beneficial influence of exosomes in enhancing the neural microenvironment following neurological diseases, offering promise for improved neural recovery and management in these conditions.
Collapse
Affiliation(s)
- Arefe Rasouli
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammadbagher Hosseini
- Department of Pediatrics, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Pourmohammadfazel
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
| | | |
Collapse
|
19
|
Chen WF, Chuang JMJ, Yang SN, Chen NF, Bhattacharya M, Liu HT, Dhama K, Chakraborty C, Wen ZH. Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide‑resistant glioblastoma. Oncol Lett 2024; 28:378. [PMID: 38939621 PMCID: PMC11209862 DOI: 10.3892/ol.2024.14511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 04/09/2024] [Indexed: 06/29/2024] Open
Abstract
Glioblastoma multiforme (GBM) is an aggressive brain cancer that occurs more frequently than other brain tumors. The present study aimed to reveal a novel mechanism of temozolomide resistance in GBM using bioinformatics and wet lab analyses, including meta-Z analysis, Kaplan-Meier survival analysis, protein-protein interaction (PPI) network establishment, cluster analysis of co-expressed gene networks, and hierarchical clustering of upregulated and downregulated genes. Next-generation sequencing and quantitative PCR analyses revealed downregulated [tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 1 (TIE1), calcium voltage-gated channel auxiliary subunit α2Δ1 (CACNA2D1), calpain 6 (CAPN6) and a disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6)] and upregulated [serum amyloid (SA)A1, SAA2, growth differentiation factor 15 (GDF15) and ubiquitin specific peptidase 26 (USP26)] genes. Different statistical models were developed for these genes using the Z-score for P-value conversion, and Kaplan-Meier plots were constructed using several patient cohorts with brain tumors. The highest number of nodes was observed in the PPI network was for ADAMTS6 and TIE1. The PPI network model for all genes contained 35 nodes and 241 edges. Immunohistochemical staining was performed using isocitrate dehydrogenase (IDH)-wild-type or IDH-mutant GBM samples from patients and a significant upregulation of TIE1 (P<0.001) and CAPN6 (P<0.05) protein expression was demonstrated in IDH-mutant GBM in comparison with IDH-wild-type GBM. Structural analysis revealed an IDH-mutant model demonstrating the mutant residues (R132, R140 and R172). The findings of the present study will help the future development of novel biomarkers and therapeutics for brain tumors.
Collapse
Affiliation(s)
- Wu-Fu Chen
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, R.O.C
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, R.O.C
| | - Jimmy Ming-Jung Chuang
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, R.O.C
| | - San-Nan Yang
- Department of Pediatrics, E-DA Hospital, School of Medicine, College of Medicine I-Shou University, Kaohsiung 82445, Taiwan, R.O.C
- School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan, R.O.C
| | - Nan-Fu Chen
- Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan, R.O.C
- Center for General Education, Cheng Shiu University, Kaohsiung 833301, Taiwan, R.O.C
| | | | - Hsin-Tzu Liu
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan, R.O.C
| | - Kuldeep Dhama
- Division of Pathology, Indian Council of Agriculture Research-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243122, India
| | - Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal 700126, India
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, R.O.C
| |
Collapse
|
20
|
Xu C, Jiang C, Li Z, Gao H, Xian J, Guo W, He D, Peng X, Zhou D, Li D. Exosome nanovesicles: biomarkers and new strategies for treatment of human diseases. MedComm (Beijing) 2024; 5:e660. [PMID: 39015555 PMCID: PMC11247338 DOI: 10.1002/mco2.660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/18/2024] Open
Abstract
Exosomes are nanoscale vesicles of cellular origin. One of the main characteristics of exosomes is their ability to carry a wide range of biomolecules from their parental cells, which are important mediators of intercellular communication and play an important role in physiological and pathological processes. Exosomes have the advantages of biocompatibility, low immunogenicity, and wide biodistribution. As researchers' understanding of exosomes has increased, various strategies have been proposed for their use in diagnosing and treating diseases. Here, we provide an overview of the biogenesis and composition of exosomes, describe the relationship between exosomes and disease progression, and focus on the use of exosomes as biomarkers for early screening, disease monitoring, and guiding therapy in refractory diseases such as tumors and neurodegenerative diseases. We also summarize the current applications of exosomes, especially engineered exosomes, for efficient drug delivery, targeted therapies, gene therapies, and immune vaccines. Finally, the current challenges and potential research directions for the clinical application of exosomes are also discussed. In conclusion, exosomes, as an emerging molecule that can be used in the diagnosis and treatment of diseases, combined with multidisciplinary innovative solutions, will play an important role in clinical applications.
Collapse
Affiliation(s)
- Chuan Xu
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| | - Chaoyang Jiang
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| | - Zhihui Li
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| | - Hui Gao
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| | - Jing Xian
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| | - Wenyan Guo
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| | - Dan He
- Department of OncologyThe Second Affiliated Hospital of Chengdu Medical CollegeChina National Nuclear Corporation 416 HospitalChengduSichuanChina
| | - Xingchen Peng
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Daijun Zhou
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| | - Dong Li
- Department of OncologyThe General Hospital of Western Theater CommandChengduChina
| |
Collapse
|
21
|
Durmaz E, Dribika L, Kutnyanszky M, Mead B. Utilizing extracellular vesicles as a drug delivery system in glaucoma and RGC degeneration. J Control Release 2024; 372:209-220. [PMID: 38880332 DOI: 10.1016/j.jconrel.2024.06.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 06/18/2024]
Abstract
Retinal diseases are the leading cause of blindness, resulting in irreversible degeneration and death of retinal neurons. One such cell type, the retinal ganglion cell (RGC), is responsible for connecting the retina to the rest of the brain through its axons that make up the optic nerve and is the primary cell lost in glaucoma and traumatic optic neuropathy. To date, different therapeutic strategies have been investigated to protect RGCs from death and preserve vision, yet currently available strategies are restricted to treating neuron loss by reducing intraocular pressure. A major barrier identified by these studies is drug delivery to RGCs, which is in large part due to drug stability, short duration time at target, low delivery efficiency, and undesired off-target effects. Therefore, a delivery system to deal with these problems is needed to ensure maximum benefit from the candidate therapeutic material. Extracellular vesicles (EV), nanocarriers released by all cells, are lipid membranes encapsulating RNAs, proteins, and lipids. As they naturally shuttle these encapsulated compounds between cells for communicative purposes, they may be exploitable and offer opportunities to overcome hurdles in retinal drug delivery, including drug stability, drug molecular weight, barriers in the retina, and drug adverse effects. Here, we summarize the potential of an EV drug delivery system, discussing their superiorities and potential application to target RGCs.
Collapse
Affiliation(s)
- Esmahan Durmaz
- Cardiff University, School of Optometry & Vision Sciences, Cardiff, UK.
| | | | | | - Ben Mead
- Cardiff University, School of Optometry & Vision Sciences, Cardiff, UK.
| |
Collapse
|
22
|
Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, Ramezani M. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med Res Rev 2024; 44:1596-1661. [PMID: 38299924 DOI: 10.1002/med.22023] [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: 12/08/2022] [Revised: 11/28/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.
Collapse
Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
23
|
Razavinia A, Razavinia A, Jamshidi Khalife Lou R, Ghavami M, Shahri F, Tafazoli A, Khalesi B, Hashemi ZS, Khalili S. Exosomes as novel tools for renal cell carcinoma therapy, diagnosis, and prognosis. Heliyon 2024; 10:e32875. [PMID: 38948044 PMCID: PMC11211897 DOI: 10.1016/j.heliyon.2024.e32875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/06/2024] [Accepted: 06/11/2024] [Indexed: 07/02/2024] Open
Abstract
Background Renal Cell Carcinoma (RCC) stands as a formidable challenge within the field of oncology, despite considerable research endeavors. The advanced stages of this malignancy present formidable barriers to effective treatment and management. Objective This review aims to explore the potential of exosomes in addressing the diagnostic and therapeutic challenges associated with RCC. Specifically, it investigates the role of exosomes as biomarkers and therapeutic vehicles in the context of RCC management. Methods For this review article, a comprehensive literature search was conducted using databases such as PubMed, employing relevant keywords to identify research articles pertinent to the objectives of the review. Initially, 200 articles were identified, which underwent screening to remove duplicates and assess relevance based on titles and abstracts, followed by a detailed examination of full texts. From the selected articles, relevant data were extracted and synthesized to address the review's objectives. The conclusions were drawn based on a thorough analysis of the findings. The quality was ensured through independent review and resolution of discrepancies among multiple reviewers. Results Exosomes demonstrate potential as diagnostic tools for early detection, prognosis, and treatment monitoring in RCC. Their ability to deliver various therapeutic agents, such as small interfering RNAs, lncRNAs, chemotherapeutic drugs, and immune-stimulating agents, allows for a personalized approach to RCC management. By leveraging exosome-based technologies, precision and efficacy in treatment strategies can be significantly enhanced. Conclusion Despite the promising advancements enabled by exosomes in the management of RCC, further research is necessary to refine exosome-based technologies and validate their efficacy, safety, and long-term benefits through rigorous clinical trials. Embracing exosomes as integral components of RCC diagnosis and treatment represents a significant step towards improving patient outcomes and addressing the persistent challenges posed by this malignancy in the field of oncology.
Collapse
Affiliation(s)
- Amir Razavinia
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Abazar Razavinia
- Genetics Department, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Roya Jamshidi Khalife Lou
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahlegha Ghavami
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada
| | - Forouzan Shahri
- Department of Chemistry, Faculty of Sciences, University of Guilan, Iran
| | - Aida Tafazoli
- Department of Bacterial and Virology, Shiraz medical school, Shiraz, Iran
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization, Karaj 3197619751, Iran
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
| |
Collapse
|
24
|
Yang Z, Wu H, Wang Z, Bian E, Zhao B. The role and application of small extracellular vesicles in glioma. Cancer Cell Int 2024; 24:229. [PMID: 38951882 PMCID: PMC11218314 DOI: 10.1186/s12935-024-03389-z] [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: 01/08/2024] [Accepted: 05/28/2024] [Indexed: 07/03/2024] Open
Abstract
Small extracellular vesicles (sEVs) are cell-derived, nanometer-sized particles enclosed by a lipid bilayer. All kinds of biological molecules, including proteins, DNA fragments, RNA, lipids, and metabolites, can be selectively loaded into sEVs and transmitted to recipient cells that are near and distant. Growing shreds of evidence show the significant biological function and the clinical significance of sEVs in cancers. Numerous recent studies have validated that sEVs play an important role in tumor progression and can be utilized to diagnose, stage, grading, and monitor early tumors. In addition, sEVs have also served as drug delivery nanocarriers and cancer vaccines. Although it is still infancy, the field of basic and translational research based on sEVs has grown rapidly. In this review, we summarize the latest research on sEVs in gliomas, including their role in the malignant biological function of gliomas, and the potential of sEVs in non-invasive diagnostic and therapeutic approaches, i.e., as nanocarriers for drug or gene delivery and cancer vaccines.
Collapse
Affiliation(s)
- Zhihao Yang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China
| | - HaoYuan Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China
| | - ZhiWei Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China
| | - ErBao Bian
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China.
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China.
| | - Bing Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China.
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China.
| |
Collapse
|
25
|
Gil-Chinchilla JI, Zapata AG, Moraleda JM, García-Bernal D. Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects. Biomolecules 2024; 14:734. [PMID: 39062449 PMCID: PMC11275142 DOI: 10.3390/biom14070734] [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: 05/08/2024] [Revised: 06/11/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.
Collapse
Affiliation(s)
- Jesús I. Gil-Chinchilla
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
| | - Agustín G. Zapata
- Department of Cell Biology, Complutense University, 28040 Madrid, Spain;
| | - Jose M. Moraleda
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Medicine, University of Murcia, 30120 Murcia, Spain
| | - David García-Bernal
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Biochemistry, Molecular Biology and Immunology, University of Murcia, 30120 Murcia, Spain
| |
Collapse
|
26
|
Lavi Arab F, Hoseinzadeh A, Hafezi F, Sadat Mohammadi F, Zeynali F, Hadad Tehran M, Rostami A. Mesenchymal stem cell-derived exosomes for management of prostate cancer: An updated view. Int Immunopharmacol 2024; 134:112171. [PMID: 38701539 DOI: 10.1016/j.intimp.2024.112171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 04/16/2024] [Accepted: 04/27/2024] [Indexed: 05/05/2024]
Abstract
Prostate cancer represents the second most prevalent form of cancer found in males, and stands as the fifth primary contributor to cancer-induced mortality on a global scale. Research has shown that transplanted mesenchymal stem cells (MSCs) can migrate by homing to tumor sites in the body. In prostate cancer, researchers have explored the fact that MSC-based therapies (including genetically modified delivery vehicles or vectors) and MSC-derived exosomes are emerging as attractive options to improve the efficacy and safety of traditional cancer therapies. In addition, researchers have reported new insights into the application of extracellular vesicle (EV)-MSC therapy as a novel treatment option that could provide a more effective and targeted approach to prostate cancer treatment. Moreover, the new generation of exosomes, which contain biologically functional molecules as signal transducers between cells, can simultaneously deliver different therapeutic agents and induce an anti-tumor phenotype in immune cells and their recruitment to the tumor site. The results of the current research on the use of MSCs in the treatment of prostate cancer may be helpful to researchers and clinicians working in this field. Nevertheless, it is crucial to emphasize that although dual-role MSCs show promise as a therapeutic modality for managing prostate cancer, further investigation is imperative to comprehensively grasp their safety and effectiveness. Ongoing clinical trials are being conducted to assess the viability of MSCs in the management of prostate cancer. The results of these trials will help determine the viability of this approach. Based on the current literature, engineered MSCs-EV offer great potential for application in targeted tumor therapy.
Collapse
Affiliation(s)
- Fahimeh Lavi Arab
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Akram Hoseinzadeh
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.; Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Hafezi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Sadat Mohammadi
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farid Zeynali
- Department of Urology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Melika Hadad Tehran
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Amirreza Rostami
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
27
|
Stawarska A, Bamburowicz-Klimkowska M, Runden-Pran E, Dusinska M, Cimpan MR, Rios-Mondragon I, Grudzinski IP. Extracellular Vesicles as Next-Generation Diagnostics and Advanced Therapy Medicinal Products. Int J Mol Sci 2024; 25:6533. [PMID: 38928240 PMCID: PMC11204223 DOI: 10.3390/ijms25126533] [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: 04/26/2024] [Revised: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Extracellular vesicles (EVs) hold great promise for clinical application as new diagnostic and therapeutic modalities. This paper describes major GMP-based upstream and downstream manufacturing processes for EV large-scale production, also focusing on post-processing technologies such as surface bioengineering and uploading studies to yield novel EV-based diagnostics and advanced therapy medicinal products. This paper also focuses on the quality, safety, and efficacy issues of the bioengineered EV drug candidates before first-in-human studies. Because clinical trials involving extracellular vesicles are on the global rise, this paper encompasses different clinical studies registered on clinical-trial register platforms, with varying levels of advancement, highlighting the growing interest in EV-related clinical programs. Navigating the regulatory affairs of EVs poses real challenges, and obtaining marketing authorization for EV-based medicines remains complex due to the lack of specific regulatory guidelines for such novel products. This paper discusses the state-of-the-art regulatory knowledge to date on EV-based diagnostics and medicinal products, highlighting further research and global regulatory needs for the safe and reliable implementation of bioengineered EVs as diagnostic and therapeutic tools in clinical settings. Post-marketing pharmacovigilance for EV-based medicinal products is also presented, mainly addressing such topics as risk assessment and risk management.
Collapse
Affiliation(s)
- Agnieszka Stawarska
- Department of Toxicology and Food Science, Faculty of Pharmacy, Medical University of Warsaw, Banacha Str. 1, 02-097 Warsaw, Poland; (M.B.-K.); (I.P.G.)
| | - Magdalena Bamburowicz-Klimkowska
- Department of Toxicology and Food Science, Faculty of Pharmacy, Medical University of Warsaw, Banacha Str. 1, 02-097 Warsaw, Poland; (M.B.-K.); (I.P.G.)
| | - Elise Runden-Pran
- Health Effects Laboratory, Department of Environmental Chemistry, Norwegian Institute for Air Research, 2007 Kjeller, Norway; (E.R.-P.); (M.D.)
| | - Maria Dusinska
- Health Effects Laboratory, Department of Environmental Chemistry, Norwegian Institute for Air Research, 2007 Kjeller, Norway; (E.R.-P.); (M.D.)
| | - Mihaela Roxana Cimpan
- Biomaterials—Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien Str. 19, 5009 Bergen, Norway; (M.R.C.); (I.R.-M.)
| | - Ivan Rios-Mondragon
- Biomaterials—Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien Str. 19, 5009 Bergen, Norway; (M.R.C.); (I.R.-M.)
| | - Ireneusz P. Grudzinski
- Department of Toxicology and Food Science, Faculty of Pharmacy, Medical University of Warsaw, Banacha Str. 1, 02-097 Warsaw, Poland; (M.B.-K.); (I.P.G.)
| |
Collapse
|
28
|
Afridi S, Sharma P, Choudhary F, Rizwan A, Nizam A, Parvez A, Farooqi H. Extracellular Vesicles: A New Approach to Study the Brain's Neural System and Its Diseases. Cell Biochem Biophys 2024; 82:521-534. [PMID: 38727784 DOI: 10.1007/s12013-024-01271-3] [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: 04/08/2024] [Indexed: 08/25/2024]
Abstract
In normal and pathophysiological conditions our cells secrete vesicular bodies known as extracellular particles. Extracellular vesicles are lipid-bound extracellular particles. A majority of these extracellular vesicles are linked to cell-to-cell communication. Brain consists of tightly packed neural cells. Neural cell releases extracellular vesicles in cerebrospinal fluid. Extracellular vesicle mediated crosstalk maintains neural homeostasis in the central nervous system via transferring cargos between neural cells. In neurodegenerative diseases, small extracellular vesicle transfer misfolded proteins to healthy cells in the neural microenvironment. They can also cross blood-brain barrier (BBB) and stimulate peripheral immune response inside central nervous system. In today's world different approaches employ extracellular vesicle in various therapeutics. This review gives a brief knowledge about the biological relevance of extracellular vesicles in the central nervous system and relevant advances in the translational application of EV in brain disorders.
Collapse
Affiliation(s)
- Shahid Afridi
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Pradakshina Sharma
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Furqan Choudhary
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Amber Rizwan
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Anam Nizam
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Adil Parvez
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Humaira Farooqi
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India.
| |
Collapse
|
29
|
Che Shaffi S, Hairuddin ON, Mansor SF, Syafiq TMF, Yahaya BH. Unlocking the Potential of Extracellular Vesicles as the Next Generation Therapy: Challenges and Opportunities. Tissue Eng Regen Med 2024; 21:513-527. [PMID: 38598059 PMCID: PMC11087396 DOI: 10.1007/s13770-024-00634-4] [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: 11/14/2022] [Revised: 08/25/2023] [Accepted: 08/25/2023] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have undergone extensive investigation for their potential therapeutic applications, primarily attributed to their paracrine activity. Recently, researchers have been exploring the therapeutic potential of extracellular vesicles (EVs) released by MSCs. METHODS MEDLINE/PubMed and Google scholar databases were used for the selection of literature. The keywords used were mesenchymal stem cells, extracellular vesicles, clinical application of EVs and challenges EVs production. RESULTS These EVs have demonstrated robust capabilities in transporting intracellular cargo, playing a critical role in facilitating cell-to-cell communication by carrying functional molecules, including proteins, RNA species, DNAs, and lipids. Utilizing EVs as an alternative to stem cells offers several benefits, such as improved safety, reduced immunogenicity, and the ability to traverse biological barriers. Consequently, EVs have emerged as an increasingly attractive option for clinical use. CONCLUSION From this perspective, this review delves into the advantages and challenges associated with employing MSC-EVs in clinical settings, with a specific focus on their potential in treating conditions like lung diseases, cancer, and autoimmune disorders.
Collapse
Affiliation(s)
- Syahidatulamali Che Shaffi
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
| | - Omar Nafiis Hairuddin
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
| | - Siti Farizan Mansor
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
- Faculty of Health Sciences, Universiti Teknologi MARA, Cawangan Pulau Pinang, Kampus Bertam, 13200, Kepala Batas, Penang, Malaysia
| | - Tengku Muhamad Faris Syafiq
- IIUM Molecular and Cellular Biology Research, Department of Basic Medical Sciences, Kulliyyah of Nursing, International Islamic University Malaysia, 25100, Kuantan, Pahang, Malaysia
| | - Badrul Hisham Yahaya
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia.
| |
Collapse
|
30
|
Di Francesco V, Chua AJ, Huang D, D'Souza A, Yang A, Bleier BS, Amiji MM. RNA therapies for CNS diseases. Adv Drug Deliv Rev 2024; 208:115283. [PMID: 38494152 DOI: 10.1016/j.addr.2024.115283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 03/19/2024]
Abstract
Neurological disorders are a diverse group of conditions that pose an increasing health burden worldwide. There is a general lack of effective therapies due to multiple reasons, of which a key obstacle is the presence of the blood-brain barrier, which limits drug delivery to the central nervous system, and generally restricts the pool of candidate drugs to small, lipophilic molecules. However, in many cases, these are unable to target key pathways in the pathogenesis of neurological disorders. As a group, RNA therapies have shown tremendous promise in treating various conditions because they offer unique opportunities for specific targeting by leveraging Watson-Crick base pairing systems, opening up possibilities to modulate pathological mechanisms that previously could not be addressed by small molecules or antibody-protein interactions. This potential paradigm shift in disease management has been enabled by recent advances in synthesizing, purifying, and delivering RNA. This review explores the use of RNA-based therapies specifically for central nervous system disorders, where we highlight the inherent limitations of RNA therapy and present strategies to augment the effectiveness of RNA therapeutics, including physical, chemical, and biological methods. We then describe translational challenges to the widespread use of RNA therapies and close with a consideration of future prospects in this field.
Collapse
Affiliation(s)
- Valentina Di Francesco
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Andy J Chua
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA; Department of Otorhinolaryngology - Head and Neck Surgery, Sengkang General Hospital, 110 Sengkang E Way, 544886, Singapore
| | - Di Huang
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Anisha D'Souza
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Alicia Yang
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Benjamin S Bleier
- Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Mansoor M Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Chemical Engineering, College of Engineering, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA.
| |
Collapse
|
31
|
Wang C, Li M, Xia X, Fu Y, Wang Y, Xu W, Wei H, Wei L. Construction of exosome-loaded LL-37 and its protection against zika virus infection. Antiviral Res 2024; 225:105855. [PMID: 38460762 DOI: 10.1016/j.antiviral.2024.105855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/21/2024] [Accepted: 03/03/2024] [Indexed: 03/11/2024]
Abstract
Zika virus (ZIKV) is an enveloped, single-stranded and positive-stranded RNA virus of the genus Flavivirus in the family Flaviviridae. ZIKV can cross the placental barrier and infect the fetus, causing microcephaly, congenital ZIKV syndrome, and even fetal death. ZIKV infection can also lead to testicular damage and male sterility. But no effective drugs and vaccines are available up to now. Previous studies have shown that the cathelicidin antimicrobial peptide LL-37 can protect against ZIKV infection. However, LL-37 is a secreted peptide, which can be easily degraded in vivo. We herein constructed exosome-loaded LL-37 (named LL-37-TM-exo and TM-LL-37-exo) using the transmembrane protein TM to load LL-37 onto the membrane of exosome. We found that exosome-loaded LL-37 could significantly inhibit ZIKV infection in vitro and in vivo, and LL-37-TM-exo had stronger antiviral activity than that of TM-LL-37-exo, which could significantly reduce ZIKV-induced testicular injury and sperm injury, and had broad-spectrum antiviral effect. Compared to free LL-37, exosome-loaded LL-37 showed a better serum stability, higher efficiency to cross the placental barrier, and stronger antiviral activity. The mechanism of exosome-loaded LL-37 against ZIKV infection was consistent with that of free LL-37, which could directly inactivate viral particles, reduce the susceptibility of host cells, and act on viral replication stage. Our study provides a novel strategy for the development of LL-37 against viral infection.
Collapse
Affiliation(s)
- Chen Wang
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Min Li
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Xiaohui Xia
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Yuxuan Fu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Yi Wang
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Wei Xu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Hongqi Wei
- Department of Otolaryngology, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, 215123, China.
| | - Lin Wei
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China; School of Life Sciences, Anhui Medical University, Hefei, Anhui, 230032, China.
| |
Collapse
|
32
|
Soroush A, Pourhossein S, Hosseingholizadeh D, Hjazi A, Shahhosseini R, Kavoosi H, Kermanshahi N, Behnamrad P, Ghavamikia N, Dadashpour M, Karkon Shayan S. Anti-cancer potential of zerumbone in cancer and glioma: current trends and future perspectives. Med Oncol 2024; 41:125. [PMID: 38652207 DOI: 10.1007/s12032-024-02327-3] [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: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 04/25/2024]
Abstract
Plant-derived immunomodulators and antitumor factors have appealed lots of attention from natural product scientists for their efficiency and safety and their important contribution to well-designed targeted drug action and delivery mechanisms. Zerumbone (ZER), the chief component of Zingiber zerumbet rhizomes, has been examined for its wide-spectrum in the treatment of multi-targeted diseases. The rhizomes have been used as food flavoring agents in numerous cuisines and in flora medication. Numerous in vivo and in vitro experiments have prepared confirmation of ZER as a potent immunomodulator as well as a potential anti-tumor agent. This review is an interesting compilation of all the important results of the research carried out to date to investigate the immunomodulatory and anticancer properties of ZER. The ultimate goal of this comprehensive review is to supply updated information and a crucial evaluation on ZER, including its chemistry and immunomodulating and antitumour properties, which may be of principal importance to supply a novel pathway for subsequent investigation to discover new agents to treat cancers and immune-related sickness. In addition, updated information on the toxicology of ZER has been summarized to support its safety profile.
Collapse
Affiliation(s)
| | - Siavash Pourhossein
- Department of Pharmacy, Eastern Mediterranean University, via Mersin 10, Famagusta, North Cyprus, Turkey
| | | | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | | | - Haniyeh Kavoosi
- Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Nazgol Kermanshahi
- Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Parisa Behnamrad
- Department of Pharmaceutics, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Nima Ghavamikia
- Cardiology Department, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mehdi Dadashpour
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
- Semnan University of Medical Sciences, Semnan, Iran.
| | | |
Collapse
|
33
|
Padinharayil H, Varghese J, Wilson C, George A. Mesenchymal stem cell-derived exosomes: Characteristics and applications in disease pathology and management. Life Sci 2024; 342:122542. [PMID: 38428567 DOI: 10.1016/j.lfs.2024.122542] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/03/2024]
Abstract
Mesenchymal stem cells (MSCs) possess a role in tissue regeneration and homeostasis because of inherent immunomodulatory capacity and the production of factors that encourage healing. There is substantial evidence that MSCs' therapeutic efficacy is primarily determined by their paracrine function including in cancers. Extracellular vesicles (EVs) are basic paracrine effectors of MSCs that reside in numerous bodily fluids and cell homogenates and play an important role in bidirectional communication. MSC-derived EVs (MSC-EVs) offer a wide range of potential therapeutic uses that exceed cell treatment, while maintaining protocell function and having less immunogenicity. We describe characteristics and isolation methods of MSC-EVs, and focus on their therapeutic potential describing its roles in tissue repair, anti-fibrosis, and cancer with an emphasis on the molecular mechanism and immune modulation and clinical trials. We also explain current understanding and challenges in the clinical applications of MSC-EVs as a cell free therapy.
Collapse
Affiliation(s)
- Hafiza Padinharayil
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 05, Kerala, India; PG & Research Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta, Kerala 689641, India
| | - Jinsu Varghese
- PG & Research Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta, Kerala 689641, India
| | - Cornelia Wilson
- Canterbury Christ Church University, Natural Applied Sciences, Life Science Industry Liaison Lab, Discovery Park, Sandwich CT139FF, United Kingdom.
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 05, Kerala, India.
| |
Collapse
|
34
|
Singh RR, Mondal I, Janjua T, Popat A, Kulshreshtha R. Engineered smart materials for RNA based molecular therapy to treat Glioblastoma. Bioact Mater 2024; 33:396-423. [PMID: 38059120 PMCID: PMC10696434 DOI: 10.1016/j.bioactmat.2023.11.007] [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: 04/25/2023] [Revised: 10/19/2023] [Accepted: 11/14/2023] [Indexed: 12/08/2023] Open
Abstract
Glioblastoma (GBM) is an aggressive malignancy of the central nervous system (CNS) that remains incurable despite the multitude of improvements in cancer therapeutics. The conventional chemo and radiotherapy post-surgery have only been able to improve the prognosis slightly; however, the development of resistance and/or tumor recurrence is almost inevitable. There is a pressing need for adjuvant molecular therapies that can successfully and efficiently block tumor progression. During the last few decades, non-coding RNAs (ncRNAs) have emerged as key players in regulating various hallmarks of cancer including that of GBM. The levels of many ncRNAs are dysregulated in cancer, and ectopic modulation of their levels by delivering antagonists or overexpression constructs could serve as an attractive option for cancer therapy. The therapeutic potential of several types of ncRNAs, including miRNAs, lncRNAs, and circRNAs, has been validated in both in vitro and in vivo models of GBM. However, the delivery of these RNA-based therapeutics is highly challenging, especially to the tumors of the brain as the blood-brain barrier (BBB) poses as a major obstacle, among others. Also, since RNA is extremely fragile in nature, careful considerations must be met while designing a delivery agent. In this review we have shed light on how ncRNA therapy can overcome the limitations of its predecessor conventional therapy with an emphasis on smart nanomaterials that can aide in the safe and targeted delivery of nucleic acids to treat GBM. Additionally, critical gaps that currently exist for successful transition from viral to non-viral vector delivery systems have been identified. Finally, we have provided a perspective on the future directions, potential pathways, and target areas for achieving rapid clinical translation of, RNA-based macromolecular therapy to advance the effective treatment of GBM and other related diseases.
Collapse
Affiliation(s)
- Ravi Raj Singh
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- University of Queensland –IIT Delhi Academy of Research (UQIDAR)
| | - Indranil Mondal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
| | - Taskeen Janjua
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- Department of Functional Materials and Catalysis, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
| |
Collapse
|
35
|
Jegathesan Y, Stephen PP, Sati ISEE, Narayanan P, Monif M, Kamarudin MNA. MicroRNAs in adult high-grade gliomas: Mechanisms of chemotherapeutic resistance and their clinical relevance. Biomed Pharmacother 2024; 172:116277. [PMID: 38377734 DOI: 10.1016/j.biopha.2024.116277] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/11/2024] [Accepted: 02/13/2024] [Indexed: 02/22/2024] Open
Abstract
Notorious for its high mortality rate, the current standard treatment for high-grade gliomas remains a challenge. This is largely due to the complex heterogeneity of the tumour coupled with dysregulated molecular mechanisms leading to the development of drug resistance. In recent years, microRNAs (miRNAs) have been considered to provide important information about the pathogenesis and prognostication of gliomas. miRNAs have been shown to play a specific role in promoting oncogenesis and regulating resistance to anti-glioma therapeutic agents through diverse cellular mechanisms. These include regulation of apoptosis, alterations in drug efflux pathways, enhanced activation of oncogenic signalling pathways, Epithelial-Mesenchymal Transition-like process (EMT-like) and a few others. With this knowledge, upregulation or inhibition of selected miRNAs can be used to directly affect drug resistance in glioma cells. Moreover, the clinical use of miRNAs in glioma management is becoming increasingly valuable. This comprehensive review delves into the role of miRNAs in drug resistance in high-grade gliomas and underscores their clinical significance. Our analysis has identified a distinct cluster of oncogenic miRNAs (miR-9, miR-21, miR-26a, miR-125b, and miR-221/222) and tumour suppressive miRNAs (miR-29, miR-23, miR-34a-5p, miR 181b-5p, miR-16-5p, and miR-20a) that consistently emerge as key players in regulating drug resistance across various studies. These miRNAs have demonstrated significant clinical relevance in the context of resistance to anti-glioma therapies. Additionally, the clinical significance of miRNA analysis is emphasised, including their potential to serve as clinical biomarkers for diagnosing, staging, evaluating prognosis, and assessing treatment response in gliomas.
Collapse
Affiliation(s)
- Yugendran Jegathesan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia; Taiping Hospital, Jalan Taming Sari, Perak, Taiping 34000, Malaysia
| | - Pashaun Paveen Stephen
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia; Coffs Harbour Health Campus, Coffs Harbour, NSW 2450, Australia
| | - Isra Saif Eldin Eisa Sati
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia
| | - Prakrithi Narayanan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia
| | - Mastura Monif
- Department of Neuroscience, Central Clinical School, Monash University, VIC, Melbourne, Australia; Department of Physiology, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Neurology, The Alfred, Melbourne, VIC, Australia
| | - Muhamad Noor Alfarizal Kamarudin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia.
| |
Collapse
|
36
|
Liguori GL. Challenges and Promise for Glioblastoma Treatment through Extracellular Vesicle Inquiry. Cells 2024; 13:336. [PMID: 38391949 PMCID: PMC10886570 DOI: 10.3390/cells13040336] [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: 12/15/2023] [Revised: 01/31/2024] [Accepted: 02/08/2024] [Indexed: 02/24/2024] Open
Abstract
Glioblastoma (GB) is a rare but extremely aggressive brain tumor that significantly impacts patient outcomes, affecting both duration and quality of life. The protocol established by Stupp and colleagues in 2005, based on radiotherapy and chemotherapy with Temozolomide, following maximum safe surgical resection remains the gold standard for GB treatment; however, it is evident nowadays that the extreme intratumoral and intertumoral heterogeneity, as well as the invasiveness and tendency to recur, of GB are not compatible with a routine and unfortunately ineffective treatment. This review article summarizes the main challenges in the search for new valuable therapies for GB and focuses on the impact that extracellular vesicle (EV) research and exploitation may have in the field. EVs are natural particles delimited by a lipidic bilayer and filled with functional cellular content that are released and uptaken by cells as key means of cell communication. Furthermore, EVs are stable in body fluids and well tolerated by the immune system, and are able to cross physiological, interspecies, and interkingdom barriers and to target specific cells, releasing inherent or externally loaded functionally active molecules. Therefore, EVs have the potential to be ideal allies in the fight against GB and to improve the prognosis for GB patients. The present work describes the main preclinical results obtained so far on the use of EVs for GB treatment, focusing on both the EV sources and molecular cargo used in the various functional studies, primarily in vivo. Finally, a SWOT analysis is performed, highlighting the main advantages and pitfalls of developing EV-based GB therapeutic strategies. The analysis also suggests the main directions to explore to realize the possibility of exploiting EVs for the treatment of GB.
Collapse
Affiliation(s)
- Giovanna L Liguori
- Institute of Genetics and Biophysics (IGB) "Adriano Buzzati-Traverso", National Research Council (CNR) of Italy, 80131 Naples, Italy
| |
Collapse
|
37
|
Dai J, Jiang Y, Hu H, Zhang S, Chen Y. Extracellular vesicles as modulators of glioblastoma progression and tumor microenvironment. Pathol Oncol Res 2024; 30:1611549. [PMID: 38379858 PMCID: PMC10876843 DOI: 10.3389/pore.2024.1611549] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/16/2024] [Indexed: 02/22/2024]
Abstract
Glioblastoma is the most aggressive brain tumor with extremely poor prognosis in adults. Routine treatments include surgery, chemotherapy, and radiotherapy; however, these may lead to rapid relapse and development of therapy-resistant tumor. Glioblastoma cells are known to communicate with macrophages, microglia, endothelial cells, astrocytes, and immune cells in the tumor microenvironment (TME) to promote tumor preservation. It was recently demonstrated that Glioblastoma-derived extracellular vesicles (EVs) participate in bidirectional intercellular communication in the TME. Apart from promoting glioblastoma cell proliferation, migration, and angiogenesis, EVs and their cargos (primarily proteins and miRNAs) can act as biomarkers for tumor diagnosis and prognosis. Furthermore, they can be used as therapeutic tools. In this review, the mechanisms of Glioblastoma-EVs biogenesis and intercellular communication with TME have been summarized. Moreover, there is discussion surrounding EVs as novel diagnostic structures and therapeutic tools for glioblastoma. Finally, unclear questions that require future investigation have been reviewed.
Collapse
Affiliation(s)
- Jie Dai
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yong Jiang
- Department of Neurosurgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Haoyue Hu
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Shuang Zhang
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yue Chen
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
38
|
Munoz JL, Einerson BD, Silver RM, Mulampurath S, Sherman LS, Rameshwar P, Prewit EB, Ramsey PS. Serum exosomal microRNA pathway activation in placenta accreta spectrum: pathophysiology and detection. AJOG GLOBAL REPORTS 2024; 4:100319. [PMID: 38440154 PMCID: PMC10910333 DOI: 10.1016/j.xagr.2024.100319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Placenta accreta spectrum disorders are a complex range of placental pathologies that are associated with significant maternal morbidity and mortality. A diagnosis of placenta accreta spectrum relies on ultrasonographic findings with modest positive predictive value. Exosomal microRNAs are small RNA molecules that reflect the cellular processes of the origin tissues. OBJECTIVE We aimed to explore exosomal microRNA expression to understand placenta accreta spectrum pathology and clinical use for placenta accreta spectrum detection. STUDY DESIGN This study was a biomarker analysis of prospectively collected samples at 2 academic institutions from 2011 to 2022. Plasma specimens were collected from patients with suspected placenta accreta spectrum, placenta previa, or repeat cesarean deliveries. Exosomes were quantified and characterized by nanoparticle tracking analysis and western blotting. MicroRNA were assessed by polymerase chain reaction array and targeted single quantification. MicroRNA pathway analysis was performed using the Ingenuity Pathway Analyses software. Placental biopsies were taken from all groups and analyzed by polymerase chain reaction and whole cell enzyme-linked immunosorbent assay. Receiver operating characteristic curve univariate analysis was performed for the use of microRNA in the prediction of placenta accreta spectrum. Clinically relevant outcomes were collected from abstracted medical records. RESULTS Plasma specimens were analyzed from a total of 120 subjects (60 placenta accreta spectrum, 30 placenta previa, and 30 control). Isolated plasma exosomes had a mean size of 71.5 nm and were 10 times greater in placenta accreta spectrum specimens (20 vs 2 particles/frame). Protein expression of exosomes was positive for intracellular adhesion molecule 1, flotilin, annexin, and CD9. MicroRNA analysis showed increased detection of 3 microRNAs (mir-92, -103, and -192) in patients with placenta accreta spectrum. Pathway interaction assessment revealed differential regulation of p53 signaling in placenta accreta spectrum and of erythroblastic oncogene B2 or human epidermal growth factor 2 in control specimens. These findings were subsequently confirmed in placental protein analysis. Placental microRNA paralleled plasma exosomal microRNA expression. Biomarker assessment of placenta accreta spectrum signature microRNA had an area under the receiver operating characteristic curve of 0.81 (P<.001; 95% confidence interval, 0.73-0.89) with a sensitivity and specificity of 89.2% and 80%, respectively. CONCLUSION In this large cohort, plasma exosomal microRNA assessment revealed differentially expressed pathways in placenta accreta spectrum, and these microRNAs are potential biomarkers for the detection of placenta accreta spectrum.
Collapse
Affiliation(s)
- Jessian L. Munoz
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX (Dr Munoz)
- Division of Fetal Intervention, Department of Obstetrics and Gynecology, Texas Children's Hospital, Houston, TX (Dr Munoz)
| | - Brett D. Einerson
- Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, UT (XX Einerson and Dr Silver)
| | - Robert M. Silver
- Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, UT (XX Einerson and Dr Silver)
| | - Sureshkumar Mulampurath
- Department of Obstetrics & Gynecology, University of Texas Health Sciences Center at San Antonio and the University Health System, San Antonio, TX (XX Mulampurath, XX Prewit, and Dr Ramsey)
| | - Lauren S. Sherman
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ (XX Sherman and XX Rameshwar)
| | - Pranela Rameshwar
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ (XX Sherman and XX Rameshwar)
| | - Egle Bytautiene Prewit
- Department of Obstetrics & Gynecology, University of Texas Health Sciences Center at San Antonio and the University Health System, San Antonio, TX (XX Mulampurath, XX Prewit, and Dr Ramsey)
| | - Patrick S. Ramsey
- Department of Obstetrics & Gynecology, University of Texas Health Sciences Center at San Antonio and the University Health System, San Antonio, TX (XX Mulampurath, XX Prewit, and Dr Ramsey)
| |
Collapse
|
39
|
Saad-Naguib MH, Kenfack Y, Sherman LS, Chafitz OB, Morelli SS. Impaired receptivity of thin endometrium: therapeutic potential of mesenchymal stem cells. Front Endocrinol (Lausanne) 2024; 14:1268990. [PMID: 38344687 PMCID: PMC10854221 DOI: 10.3389/fendo.2023.1268990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 12/26/2023] [Indexed: 02/15/2024] Open
Abstract
The endometrium is a resilient and highly dynamic tissue, undergoing cyclic renewal in preparation for embryo implantation. Cyclic endometrial regeneration depends on the intact function of several cell types, including parenchymal, endothelial, and immune cells, as well as adult stem cells that can arise from endometrial or extrauterine sources. The ability of the endometrium to undergo rapid, repeated regeneration without scarring is unique to this tissue. However, if this tissue renewal process is disrupted or dysfunctional, women may present clinically with infertility due to endometrial scarring or persistent atrophic/thin endometrium. Such disorders are rate-limiting in the treatment of female infertility and in the success of in vitro fertilization because of a dearth of treatment options specifically targeting the endometrium. A growing number of studies have explored the potential of adult stem cells, including mesenchymal stem cells (MSCs), to treat women with disorders of endometrial regeneration. MSCs are multipotent adult stem cells with capacity to differentiate into cells such as adipocytes, chondrocytes, and osteoblasts. In addition to their differentiation capacity, MSCs migrate toward injured sites where they secrete bioactive factors (e.g. cytokines, chemokines, growth factors, proteins and extracellular vesicles) to aid in tissue repair. These factors modulate biological processes critical for tissue regeneration, such as angiogenesis, cell migration and immunomodulation. The MSC secretome has therefore attracted significant attention for its therapeutic potential. In the uterus, studies utilizing rodent models and limited human trials have shown a potential benefit of MSCs and the MSC secretome in treatment of endometrial infertility. This review will explore the potential of MSCs to treat women with impaired endometrial receptivity due to a thin endometrium or endometrial scarring. We will provide context supporting leveraging MSCs for this purpose by including a review of mechanisms by which the MSC secretome promotes regeneration and repair of nonreproductive tissues.
Collapse
Affiliation(s)
- Michael H. Saad-Naguib
- Department of Obstetrics, Gynecology & Reproductive Health, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Yannick Kenfack
- Department of Medicine, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Lauren S. Sherman
- Department of Medicine, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Olivia B. Chafitz
- Department of Obstetrics & Gynecology, Hackensack University Medical Center, Hackensack, NJ, United States
| | - Sara S. Morelli
- Department of Obstetrics, Gynecology & Reproductive Health, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ, United States
| |
Collapse
|
40
|
Rezaie M, Nasehi M, Shimia M, Ebrahimnezhad M, Yousefi B, Majidinia M. Polyphenols Modulate the miRNAs Expression that Involved in Glioblastoma. Mini Rev Med Chem 2024; 24:1953-1969. [PMID: 38639278 DOI: 10.2174/0113895575304605240408105201] [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: 01/15/2024] [Revised: 03/11/2024] [Accepted: 03/16/2024] [Indexed: 04/20/2024]
Abstract
Glioblastoma multiforme (GBM), a solid tumor that develops from astrocytes, is one of the most aggressive types of brain cancer. While there have been improvements in the efficacy of treating GBM, many problems remain, especially with traditional therapy methods. Therefore, recent studies have extensively focused on developing novel therapeutic agents for combating glioblastoma. Natural polyphenols have been studied for their potential as chemopreventive and chemotherapeutic agents due to their wide range of positive qualities, including antioxidant, antiinflammatory, cytotoxic, antineoplastic, and immunomodulatory activities. These natural compounds have been suggested to act via modulated various macromolecules within cells, including microRNAs (miRNAs), which play a crucial role in the molecular milieu. In this article, we focus on how polyphenols may inhibit tumor growth by influencing the expression of key miRNAs that regulate oncogenes and tumor suppressor genes.
Collapse
Affiliation(s)
- Maede Rezaie
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Nasehi
- Cognitive and Neuroscience Research Center, Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Shimia
- Department of Neurosurgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohamad Ebrahimnezhad
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| |
Collapse
|
41
|
Li J, Lin A, Jiang R, Chen P, Xu C, Hou Y. Exosomes-mediated drug delivery for the treatment of myocardial injury. Ann Med Surg (Lond) 2024; 86:292-299. [PMID: 38222684 PMCID: PMC10783224 DOI: 10.1097/ms9.0000000000001473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 10/25/2023] [Indexed: 01/16/2024] Open
Abstract
Cardiovascular disease has become a major cause of death worldwide. Myocardial injury (MI) caused by myocardial infarction, myocarditis, and drug overdose can lead to impaired cardiac function, culminating in serious consequences such as angina pectoris, arrhythmias, and heart failure. Exosomes exhibit high biocompatibility and target specificity, rendering them an important non-cellular therapy for improving MI. Exosomes are diminutive vesicles that encapsulate nucleic acids and proteins. Exosomes derived from cardiac stem cells themselves have therapeutic effects, and they can also serve as carriers to deliver therapeutic drugs to recipient cells, thereby exerting a therapeutic effect. The molecules within exosomes are encapsulated in a lipid bilayer, allowing them to stably exist in body fluids without being affected by nucleases. Therefore, the utilization of exosomes as drug delivery systems (DDS) for disease treatment has been extensively investigated and is currently undergoing clinical trials. This review summarizes the therapeutic effects of exosomes on MI and provides an overview of current research progress on their use as DDS in MI.
Collapse
Affiliation(s)
- Jiang Li
- Zhengzhou Railway Vocational and Technical College
| | - Aiqin Lin
- Zhengzhou Railway Vocational and Technical College
| | - Rui Jiang
- Zhengzhou Railway Vocational and Technical College
| | | | - Chengyang Xu
- Henan Provincial People's Hospital, Zhengzhou, P.R. China
| | - Yuanyuan Hou
- Zhengzhou Railway Vocational and Technical College
| |
Collapse
|
42
|
Sharma S, Rana R, Prakash P, Ganguly NK. Drug target therapy and emerging clinical relevance of exosomes in meningeal tumors. Mol Cell Biochem 2024; 479:127-170. [PMID: 37016182 PMCID: PMC10072821 DOI: 10.1007/s11010-023-04715-1] [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: 11/19/2022] [Accepted: 03/17/2023] [Indexed: 04/06/2023]
Abstract
Meningioma is the most common central nervous system (CNS) tumor. In recent decades, several efforts have been made to eradicate this disease. Surgery and radiotherapy remain the standard treatment options for these tumors. Drug therapy comes to play its role when both surgery and radiotherapy fail to treat the tumor. This mostly happens when the tumors are close to vital brain structures and are nonbenign. Although a wide variety of chemotherapeutic drugs and molecular targeted drugs such as tyrosine kinase inhibitors, alkylating agents, endocrine drugs, interferon, and targeted molecular pathway inhibitors have been studied, the roles of numerous drugs remain unexplored. Recent interest is growing toward studying and engineering exosomes for the treatment of different types of cancer including meningioma. The latest studies have shown the involvement of exosomes in the theragnostic of various cancers such as the lung and pancreas in the form of biomarkers, drug delivery vehicles, and vaccines. Proper attention to this new emerging technology can be a boon in finding the consistent treatment of meningioma.
Collapse
Affiliation(s)
- Swati Sharma
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060 India
| | - Rashmi Rana
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060 India
| | - Prem Prakash
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, 110062 India
| | | |
Collapse
|
43
|
Tendulkar R, Tendulkar M. Current Update of Research on Exosomes in Cancer. Curr Mol Med 2024; 24:26-39. [PMID: 37461337 DOI: 10.2174/1566524023666230717105000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/12/2023] [Accepted: 05/25/2023] [Indexed: 08/01/2023]
Abstract
Exosomes are vesicles secreted by the plasma membrane of the cells delimited by a lipid bilayer membrane into the extracellular space of the cell. Their release is associated with the disposal mechanism to remove unwanted materials from the cells. Exosomes released from primary tumour sites migrate to other parts of the body to create a metastatic environment for spreading the tumour cells. We have reviewed that exosomes interfere with the tumour progression by (i) promoting angiogenesis, (ii) initiating metastasis, (iii) regulating tumour microenvironment (TME) and inflammation, (iv) modifying energy metabolism, and (v) transferring mutations. We have found that EVs play an important role in inducing tumour drug resistance against anticancer drugs. This review discusses the potential of exosomes to generate a significant therapeutic effect along with improved diagnosis, prognosis, insights on the various research conducted and their significant findings of our interest.
Collapse
Affiliation(s)
- Reshma Tendulkar
- Pharmaceutical Chemistry, Vivekanand Education Society's College of Pharmacy, India
| | - Mugdha Tendulkar
- Faculty of Science, Sardar Vallabhbhai College of Science, India
| |
Collapse
|
44
|
Shan C, Liang Y, Wang K, Li P. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Cancer Therapy Resistance: from Biology to Clinical Opportunity. Int J Biol Sci 2024; 20:347-366. [PMID: 38164177 PMCID: PMC10750277 DOI: 10.7150/ijbs.88500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 11/09/2023] [Indexed: 01/03/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are a type of stromal cells characterized by their properties of self-renewal and multi-lineage differentiation, which make them prominent in regenerative medicine. MSCs have shown significant potential for the treatment of various diseases, primarily through the paracrine effects mediated by soluble factors, specifically extracellular vesicles (EVs). MSC-EVs play a crucial role in intercellular communication by transferring various bioactive substances, including proteins, RNA, DNA, and lipids, highlighting the contribution of MSC-EVs in regulating cancer development and progression. Remarkably, increasing evidence indicates the association between MSC-EVs and resistance to various types of cancer treatments, including radiotherapy, chemotherapy, targeted therapy, immunotherapy, and endocrinotherapy. In this review, we provide an overview of the recent advancements in the biogenesis, isolation, and characterization of MSC-EVs, with an emphasis on their functions in cancer therapy resistance. The clinical applications and future prospects of MSC-EVs for mitigating cancer therapy resistance and enhancing drug delivery are also discussed. Elucidating the role and mechanism of MSC-EVs in the development of treatment resistance in cancer, as well as evaluating the clinical significance of MSC-EVs, is crucial for advancing our understanding of tumor biology. Meanwhile, inform the development of effective treatment strategies for cancer patients in the future.
Collapse
Affiliation(s)
- Chan Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yan Liang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| |
Collapse
|
45
|
Luo H, Jin J, Jin J, Lou K, He H, Feng S, Zeng F, Zou J. Emerging applications of extracellular vesicles in tumor therapy. Cancer Nanotechnol 2023; 14:63. [DOI: 10.1186/s12645-023-00217-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/02/2023] [Indexed: 05/29/2025] Open
Abstract
AbstractExtracellular vesicles (EVs) have tremendous potential as nano/micron-sized drug delivery carriers.
Their physical, chemical and biological characteristics distinguish them as unique carriers with specific pharmacokinetic, circulating metabolic, and biodistribution patterns in the delivery of therapeutic cargoes. They are critical mediators in the pathology of many diseases, including inflammatory diseases, fibrosis, and cancer, but they are also essential mediators in immunomodulation, cancer treatment, infectious defense, and tissue repair. In this review, we emphasize recent advances in oncology therapy using macrophage EVs, mesenchymal stem cell EVs, milk EVs, and plant EVs, as well as the advantages of EVs as delivery platforms and their prospective clinical applications and use.
Collapse
|
46
|
Harrell CR, Djonov V, Volarevic V. Mesenchymal stem cell-derived microRNAs: Friends or foes of tumor cells? Histol Histopathol 2023; 38:1373-1379. [PMID: 37306386 DOI: 10.14670/hh-18-633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Mesenchymal stem cell (MSC)-dependent biological effects in the tumor microenvironment mainly rely on the activity of MSC-sourced microRNAs (MSC-miRNAs) which modulate protein synthesis in target tumor cells, endothelial cells and tumor-infiltrated immune cells, regulating their phenotype and function. Several MSC-sourced miRNAs (miR-221, miR-23b, miR-21-5p, miR-222/223, miR-15a miR-424, miR-30b, miR-30c) possess tumor-promoting properties and are able to enhance viability, invasiveness and metastatic potential of malignant cells, induce proliferation and sprouting of tumor endothelial cells and suppress effector functions of cytotoxic tumor-infiltrated immune cells, crucially contributing to the rapid growth and progression of tumor tissue. On the contrary, MSCs also produce "anti-tumorigenic" miRNAs (miR-100, miR-222-3p, miR-146b miR-302a, miR-338-5p, miR-100-5p and miR-1246) which suppress tumor growth and progression by: Up-regulating expression of chemoresistance-related genes in tumor cells, by suppressing neo-angiogenesis and by inducing generation of tumorotoxic phenotypes in tumor-infiltrated lymphocytes. In this review article, we summarize the current knowledge about molecular mechanisms that are responsible for MSC-miRNA-dependent alterations of intracellular signaling in tumor and immune cells and we discuss different insights regarding the therapeutic potential of MSC-derived miRNAs in cancer treatment.
Collapse
Affiliation(s)
| | | | - Vladislav Volarevic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
- Department of Microbiology and Immunology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| |
Collapse
|
47
|
Pagoni M, Cava C, Sideris DC, Avgeris M, Zoumpourlis V, Michalopoulos I, Drakoulis N. miRNA-Based Technologies in Cancer Therapy. J Pers Med 2023; 13:1586. [PMID: 38003902 PMCID: PMC10672431 DOI: 10.3390/jpm13111586] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/02/2023] [Accepted: 11/04/2023] [Indexed: 11/26/2023] Open
Abstract
The discovery of therapeutic miRNAs is one of the most exciting challenges for pharmaceutical companies. Since the first miRNA was discovered in 1993, our knowledge of miRNA biology has grown considerably. Many studies have demonstrated that miRNA expression is dysregulated in many diseases, making them appealing tools for novel therapeutic approaches. This review aims to discuss miRNA biogenesis and function, as well as highlight strategies for delivering miRNA agents, presenting viral, non-viral, and exosomic delivery as therapeutic approaches for different cancer types. We also consider the therapeutic role of microRNA-mediated drug repurposing in cancer therapy.
Collapse
Affiliation(s)
- Maria Pagoni
- Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15701 Athens, Greece
| | - Claudia Cava
- Department of Science, Technology and Society, University School for Advanced Studies IUSS Pavia, 27100 Pavia, Italy;
| | - Diamantis C. Sideris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15701 Athens, Greece;
| | - Margaritis Avgeris
- Laboratory of Clinical Biochemistry—Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, “P. & A. Kyriakou” Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vassilios Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece;
| | - Ioannis Michalopoulos
- Centre of Systems Biology, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece;
| | - Nikolaos Drakoulis
- Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15701 Athens, Greece
| |
Collapse
|
48
|
Lee CS, Lee M, Na K, Hwang HS. Stem Cell-Derived Extracellular Vesicles for Cancer Therapy and Tissue Engineering Applications. Mol Pharm 2023; 20:5278-5311. [PMID: 37867343 DOI: 10.1021/acs.molpharmaceut.3c00376] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
Recently, stem cells and their secretomes have attracted great attention in biomedical applications, particularly extracellular vesicles (EVs). EVs are secretomes of cells for cell-to-cell communication. They play a role as intercellular messengers as they carry proteins, nucleic acids, lipids, and therapeutic agents. They have also been utilized as drug-delivery vehicles due to their biocompatibility, low immunogenicity, stability, targetability, and engineerable properties. The therapeutic potential of EVs can be further enhanced by surface engineering and modification using functional molecules such as aptamers, peptides, and antibodies. As a consequence, EVs hold great promise as effective delivery vehicles for enhancing treatment efficacy while avoiding side effects. Among various cell types that secrete EVs, stem cells are ideal sources of EVs because stem cells have unique properties such as self-renewal and regenerative potential for transplantation into damaged tissues that can facilitate their regeneration. However, challenges such as immune rejection and ethical considerations remain significant hurdles. Stem cell-derived EVs have been extensively explored as a cell-free approach that bypasses many challenges associated with cell-based therapy in cancer therapy and tissue regeneration. In this review, we summarize and discuss the current knowledge of various types of stem cells as a source of EVs, their engineering, and applications of EVs, focusing on cancer therapy and tissue engineering.
Collapse
Affiliation(s)
- Chung-Sung Lee
- Department of Pharmaceutical Engineering, Soonchunhyang University, Asan 31538, Republic of Korea
| | - Min Lee
- Division of Advanced Prosthodontics, University of California, Los Angeles, California 90095, United States
- Department of Bioengineering, University of California, Los Angeles, California 90095, United States
| | - Kun Na
- Department of BioMedical-Chemical Engineering, The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Hee Sook Hwang
- Department of Pharmaceutical Engineering, Dankook University, Cheonan 31116, Republic of Korea
| |
Collapse
|
49
|
Zhang X, Wang J, Liu N, Wu W, Li H, Lu W, Guo X. Umbilical Cord Blood-Derived M1 Macrophage Exosomes Loaded with Cisplatin Target Ovarian Cancer In Vivo and Reverse Cisplatin Resistance. Mol Pharm 2023; 20:5440-5453. [PMID: 37819754 DOI: 10.1021/acs.molpharmaceut.3c00132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
We investigated the therapeutic efficacy of umbilical cord blood (UCB)-derived M1 macrophage exosomes loaded with cisplatin (CIS) in ovarian cancer and platinum resistance. M1 macrophages were purified by using CD14 magnetic beads and characterized by flow cytometry. Our analyses included morphology, particle size, particle concentration, potential, drug loading capacity, counts of entry into cells, antitumor effect in vivo, and the ability to reverse drug resistance. A2780, SKOV3, and A2780/DDP, SKOV3/DDP ovarian cancer cells (CIS-sensitive and CIS-resistant cell lines, respectively) were treated with CIS or CIS-loaded M1 macrophage exosomes (M1exoCISs). The encapsulation efficiency of CIS loading into M1 macrophage exosomes was approximately 30%. In vitro, M1exoCIS treatment reduced the CIS IC50 values of both A2780, SKOV3, and A2780/DDP, SKOV3/DDP cells. We evaluated the effect of M1exoCIS on tumor growth using a mouse ovarian cancer subcutaneous transplantation tumor model inoculated with A2780/DDP cells. M1exoCIS was observed in the liver, spleen, and tumor sites 24 h posttreatment; the fluorescence intensity of M1exoCIS is higher than that of CIS. After 7 days, M1exoCIS significantly inhibited the growth of subcutaneously transplanted tumors compared with CIS alone and had a longer survival time. Moreover, the toxicity test shows that M1exoCIS has less hepatorenal toxicity than CIS. To investigate the mechanism of M1exoCIS targeting, homing, and reversing drug resistance, we performed RT-PCR, Western blotting, and Proteome Profiler Human Receptor Array analyses. We found that A2780 and A2780/DDP cells expressed the integrin β1/CD29 receptor, while M1 exosomes expressed integrin β1/CD29. In addition, M1exos carries long noncoding RNA H19, implicated in PTEN protein upregulation and miR-130a and Pgp gene downregulation, leading to the reversal of CIS drug resistance. Therefore, UCB-derived M1exoCIS target tumor sites of ovarian cancer in vivo and can be used to increase the CIS sensitivity and cytotoxicity.
Collapse
Affiliation(s)
- Xiaohui Zhang
- Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai 201204, China
| | - Jiapo Wang
- Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai 201204, China
| | - Na Liu
- Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai 201204, China
| | - Weimin Wu
- Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai 201204, China
| | - Hong Li
- Shanghai Institute of Biochemistry and Cell Biology, Shanghai 200031, China
| | - Wen Lu
- Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai 201204, China
| | - Xiaoqing Guo
- Shanghai First Maternity and Infant Hospital, Tong Ji University School of Medicine, Shanghai 201204, China
| |
Collapse
|
50
|
Shams F, Pourjabbar B, Hashemi N, Farahmandian N, Golchin A, Nuoroozi G, Rahimpour A. Current progress in engineered and nano-engineered mesenchymal stem cells for cancer: From mechanisms to therapy. Biomed Pharmacother 2023; 167:115505. [PMID: 37716113 DOI: 10.1016/j.biopha.2023.115505] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
Mesenchymal stem cells (MSCs), as self-renewing multipotent stromal cells, have been considered promising agents for cancer treatment. A large number of studies have demonstrated the valuable properties of MSC-based treatment, such as low immunogenicity and intrinsic tumor-trophic migratory properties. To enhance the potency of MSCs for therapeutic purposes, equipping MSCs with targeted delivery functions using genetic engineering is highly beneficial. Genetically engineered MSCs can express tumor suppressor agents such as pro-apoptotic, anti-proliferative, anti-angiogenic factors and act as ideal delivery vehicles. MSCs can also be loaded with nanoparticle drugs for increased efficacy and externally moderated targeting. Moreover, exosomes secreted by MSCs have important physiological properties, so they can contribute to intercellular communication and transfer cargo into targeted tumor cells. The precise role of genetically modified MSCs in tumor environments is still up for debate, but the beginning of clinical trials has been confirmed by promising results from preclinical investigations of MSC-based gene therapy for a wide range of malignancies. This review highlights the advanced techniques of engineering/nano-engineering and MSC-derived exosomes in tumor-targeted therapy.
Collapse
Affiliation(s)
- Forough Shams
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Navid Farahmandian
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Golchin
- Cellular & Molecular Research Center, Cellular & Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia 57157993313, Iran; Department of Clinical Biochemistry & Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia 57157993313, Islamic Republic of Iran
| | - Ghader Nuoroozi
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azam Rahimpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|