Advancements in extracellular vesicle therapy for neurodegenerative diseases

Abstract

Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.

Keywords

Extracellular vesicles / exosomes / Alzheimer’s disease / Parkinson’s disease / Huntington’s disease / amyotrophic lateral sclerosis / multiple sclerosis

References

[1] DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019; 14: 32.

[2] McGregor MM, Nelson AB. Circuit Mechanisms of Parkinson’s Disease. Neuron. 2019; 101: 1042-56.

[3] Saudou F, Humbert S. The Biology of Huntingtin. Neuron. 2016; 89: 910-26.

[4] Masrori P, Damme PV. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020; 27: 1918-29.

[5] Correale J, Gaitán MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017; 140: 527-46.

[6] Reed SL, Escayg A. Extracellular vesicles in the treatment of neurological disorders. Neurobiol Dis. 2021; 157: 105445.

[7] Maas SLN, Breakefield XO, Weaver AM. Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol. 2017; 27: 172-88.

[8] Hu G, Drescher KM, Chen X. Exosomal miRNAs: Biological Properties and Therapeutic Potential. Front Genet. 2012; 3: 56.

[9] Zaborowski MP, Balaj L, Breakefield XO, Lai CP. Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study. Bioscience. 2015; 65: 783-97.

[10] Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015; 4: 27066.

[11] Hu G, Yang L, Cai Y, Niu F, Mezzacappa F, Callen S, et al. Emerging roles of extracellular vesicles in neurodegenerative disorders: focus on HIV-associated neurological complications. Cell Death Dis. 2016; 7: e2481.

[12] Hu G, Gong AY, Roth AL, Huang BQ, Ward HD, Zhu G, et al. Release of luminal exosomes contributes to TLR4-mediated epithelial antimicrobial defense. PLoS Pathog. 2013; 9: e1003261.

[13] Kutchy NA, Ma R, Liu Y, Buch S, Hu G. Extracellular Vesicle-Mediated Delivery of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles to Mice Brain. Front Pharmacol. 2022; 13: 819516.

[14] Hu G, Witwer KW, Bond VC, Haughey N, Kashanchi F, Pulliam L, et al. Proceedings of the ISEV symposium on “HIV, NeuroAIDS, drug abuse & EVs”. J Extracell Vesicles. 2017; 6: 1294360.

[15] Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol. 2021; 16: 748-59.

[16] Hu G, Yelamanchili S, Kashanchi F, Haughey N, Bond VC, Witwer KW, et al. Proceedings of the 2017 ISEV symposium on “HIV, NeuroHIV, drug abuse, & EVs”. J Neurovirol. 2017; 23: 935-40.

[17] Zheng X, Zhang L, Kuang Y, Venkataramani V, Jin F, Hein K, et al. Extracellular Vesicles Derived from Neural Progenitor Cells-a Preclinical Evaluation for Stroke Treatment in Mice. Transl Stroke Res. 2021; 12: 185-203.

[18] Kumar MA, Baba SK, Sadida HQ, Marzooqi SA, Jerobin J, Altemani FH, et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther. 2024; 9: 27.

[19] Lener T, Gimona M, Aigner L, Börger V, Buzas E, Camussi G, et al. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles. 2015; 4: 30087.

[20] Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019; 88: 487-514.

[21] Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020; 367: eaau6977.

[22] Hu G, Yao H, Chaudhuri AD, Duan M, Yelamanchili SV, Wen H, et al. Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction. Cell Death Dis. 2012; 3: e381.

[23] Ma R, Kutchy NA, Wang Z, Hu G. Extracellular vesicle-mediated delivery of anti-miR-106b inhibits morphine-induced primary ciliogenesis in the brain. Mol Ther. 2023; 31: 1332-45.

[24] Buzas EI. The roles of extracellular vesicles in the immune system. Nat Rev Immunol. 2023; 23: 236-50.

[25] Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013; 200: 373-83.

[26] Clancy JW, Schmidtmann M, D’Souza-Schorey C. The ins and outs of microvesicles. FASEB Bioadv. 2021; 3: 399-406.

[27] Gurung S, Perocheau D, Touramanidou L, Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal. 2021; 19: 47.

[28] Jeppesen DK, Zhang Q, Franklin JL, Coffey RJ. Extracellular vesicles and nanoparticles: emerging complexities. Trends Cell Biol. 2023; 33: 667-81.

[29] Tricarico C, Clancy J, D’Souza-Schorey C. Biology and biogenesis of shed microvesicles. Small GTPases. 2017; 8: 220-32.

[30] Wood CR, Rosenbaum JL. Ciliary ectosomes: transmissions from the cell’s antenna. Trends Cell Biol. 2015; 25: 276-85.

[31] Ma R, Kutchy NA, Chen L, Meigs DD, Hu G. Primary cilia and ciliary signaling pathways in aging and age-related brain disorders. Neurobiol Dis. 2022; 163: 105607.

[32] Ma R, Kutchy NA, Hu G. Astrocyte-Derived Extracellular Vesicle-Mediated Activation of Primary Ciliary Signaling Contributes to the Development of Morphine Tolerance. Biol Psychiatry. 2021; 90: 575-85.

[33] Ma R, Chen L, Hu N, Caplan S, Hu G. Cilia and Extracellular Vesicles in Brain Development and Disease. Biol Psychiatry. 2024; 95: 1020-29.

[34] Gregory CD, Dransfield I. Apoptotic Tumor Cell-Derived Extracellular Vesicles as Important Regulators of the Onco-Regenerative Niche. Front Immunol. 2018; 9: 1111.

[35] Battistelli M, Falcieri E. Apoptotic Bodies: Particular Extracellular Vesicles Involved in Intercellular Communication. Biology (Basel). 2020; 9: 21.

[36] Kakarla R, Hur J, Kim YJ, Kim J, Chwae Y. Apoptotic cell-derived exosomes: messages from dying cells. Exp Mol Med. 2020; 52: 1-6.

[37] Pavlyukov MS, Yu H, Bastola S, Minata M, Shender VO, Lee Y, et al. Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors. Cancer Cell. 2018; 34: 119-35.e10.

[38] Leidal AM, Debnath J. Emerging roles for the autophagy machinery in extracellular vesicle biogenesis and secretion. FASEB Bioadv. 2021; 3: 377-86.

[39] Xing H, Tan J, Miao Y, Lv Y, Zhang Q. Crosstalk between exosomes and autophagy: A review of molecular mechanisms and therapies. J Cell Mol Med. 2021; 25: 2297-308.

[40] Manganelli V, Dini L, Tacconi S, Dinarelli S, Capozzi A, Riitano G, et al. Autophagy Promotes Enrichment of Raft Components within Extracellular Vesicles Secreted by Human 2FTGH Cells. Int J Mol Sci. 2024; 25: 6175.

[41] Sapoń K, Mańka R, Janas T, Janas T. The role of lipid rafts in vesicle formation. J Cell Sci. 2023; 136: jcs260887.

[42] Skryabin GO, Komelkov AV, Savelyeva EE, Tchevkina EM. Lipid Rafts in Exosome Biogenesis. Biochemistry (Mosc). 2020; 85: 177-91.

[43] Welsh JA, Goberdhan DCI, O’Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles. 2024; 13: e12404.

[44] Hua Y, Jiang P, Dai C, Li M. Extracellular vesicle autoantibodies. J Autoimmun. 2024; 149: 103322.

[45] Blandin A, Dugail I, Hilairet G, Ponnaiah M, Ghesquière V, Froger J, et al. Lipidomic analysis of adipose-derived extracellular vesicles reveals specific EV lipid sorting informative of the obesity metabolic state. Cell Rep. 2023; 42: 112169.

[46] Harmati M, Bukva M, Böröczky T, Buzás K, Gyukity-Sebestyén E. The role of the metabolite cargo of extracellular vesicles in tumor progression. Cancer Metastasis Rev. 2021; 40: 1203-21.

[47] Kutchy NA, Palermo A, Ma R, Li Z, Ulanov A, Callen S, et al. Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice. Metabolites. 2023; 13: 434.

[48] Sil S, Dagur RS, Liao K, Peeples ES, Hu G, Periyasamy P, et al. Strategies for the use of Extracellular Vesicles for the Delivery of Therapeutics. J Neuroimmune Pharmacol. 2020; 15: 422-42.

[49] Chivero ET, Dagur RS, Peeples ES, Sil S, Liao K, Ma R, et al. Biogenesis, physiological functions and potential applications of extracellular vesicles in substance use disorders. Cell Mol Life Sci. 2021; 78: 4849-65.

[50] Lizarraga-Valderrama LR, Sheridan GK. Extracellular vesicles and intercellular communication in the central nervous system. FEBS Lett. 2021; 595: 1391-410.

[51] Zappulli V, Friis KP, Fitzpatrick Z, Maguire CA, Breakefield XO. Extracellular vesicles and intercellular communication within the nervous system. J Clin Invest. 2016; 126: 1198-207.

[52] Solana-Balaguer J, Campoy-Campos G, Martín-Flores N, Pérez-Sisqués L, Sitjà-Roqueta L, Kucukerden M, et al. Neuron-derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB-mediated signalling and preserve neuronal complexity. J Extracell Vesicles. 2023; 12: e12355.

[53] Holm MM, Kaiser J, Schwab ME. Extracellular Vesicles: Multimodal Envoys in Neural Maintenance and Repair. Trends Neurosci. 2018; 41: 360-72.

[54] Pistono C, Bister N, Stanová I, Malm T. Glia-Derived Extracellular Vesicles: Role in Central Nervous System Communication in Health and Disease. Front Cell Dev Biol. 2021; 8: 623771.

[55] You Y, Borgmann K, Edara VV, Stacy S, Ghorpade A, Ikezu T. Activated human astrocyte-derived extracellular vesicles modulate neuronal uptake, differentiation and firing. J Extracell Vesicles. 2019; 9: 1706801.

[56] Kutchy NA, Peeples ES, Sil S, Liao K, Chivero ET, Hu G, et al. Extracellular Vesicles in Viral Infections of the Nervous System. Viruses. 2020; 12: 700.

[57] Zhang Q, Liu J, Wang W, Lin W, Ahmed W, Duan W, et al. The role of exosomes derived from stem cells in nerve regeneration: A contribution to neurological repair. Exp Neurol. 2024; 380: 114882.

[58] Huo L, Du X, Li X, Liu S, Xu Y. The Emerging Role of Neural Cell-Derived Exosomes in Intercellular Communication in Health and Neurodegenerative Diseases. Front Neurosci. 2021; 15: 738442.

[59] Liu B, Kong Y, Shi W, Kuss M, Liao K, Hu G, et al. Exosomes derived from differentiated human ADMSC with the Schwann cell phenotype modulate peripheral nerve-related cellular functions. Bioact Mater. 2021; 14: 61-75.

[60] Peng C, Trojanowski JQ, Lee VM. Protein transmission in neurodegenerative disease. Nat Rev Neurol. 2020; 16: 199-212.

[61] Muraoka S, DeLeo AM, Sethi MK, Yukawa-Takamatsu K, Yang Z, Ko J, et al. Proteomic and biological profiling of extracellular vesicles from Alzheimer’s disease human brain tissues. Alzheimers Dement. 2020; 16: 896-907.

[62] Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJA, et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis. 2011; 42: 360-7.

[63] Ananbeh H, Vodicka P, Skalnikova HK. Emerging Roles of Exosomes in Huntington’s Disease. Int J Mol Sci. 2021; 22: 4085.

[64] Wolfe MS. The role of tau in neurodegenerative diseases and its potential as a therapeutic target. Scientifica (Cairo). 2012; 2012: 796024.

[65] Pérez M, Avila J, Hernández F. Propagation of Tau via Extracellular Vesicles. Front Neurosci. 2019; 13: 698.

[66] Perbet R, Zufferey V, Leroux E, Parietti E, Espourteille J, Culebras L, et al. Tau Transfer via Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System. Cells. 2023; 12: 985.

[67] Crotti A, Sait HR, McAvoy KM, Estrada K, Ergun A, Szak S, et al. BIN1 favors the spreading of Tau via extracellular vesicles. Sci Rep. 2019; 9: 9477.

[68] Ruan Z, Pathak D, Kalavai SV, Yoshii-Kitahara A, Muraoka S, Bhatt N, et al. Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain. 2021; 144: 288-309.

[69] Calabresi P, Mechelli A, Natale G, Volpicelli-Daley L, Lazzaro GD, Ghiglieri V. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 2023; 14: 176.

[70] Ingelsson M. Alpha-Synuclein Oligomers-Neurotoxic Molecules in Parkinson’s Disease and Other Lewy Body Disorders. Front Neurosci. 2016; 10: 408.

[71] Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q, et al. Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease. Brain. 2020; 143: 1476-97.

[72] Upadhya R, Shetty AK. Extracellular Vesicles for the Diagnosis and Treatment of Parkinson’s Disease. Aging Dis. 2021; 12: 1438-50.

[73] Gustafsson G, Lööv C, Persson E, Lázaro DF, Takeda S, Bergström J, et al. Secretion and Uptake of α-Synuclein Via Extracellular Vesicles in Cultured Cells. Cell Mol Neurobiol. 2018; 38: 1539-50.

[74] Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci. 2018; 21: 1332-40.

[75] Howitt J, Hill AF. Exosomes in the Pathology of Neurodegenerative Diseases. J Biol Chem. 2016; 291: 26589-97.

[76] Yuyama K, Sun H, Mitsutake S, Igarashi Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J Biol Chem. 2012; 287: 10977-89.

[77] Picca A, Guerra F, Calvani R, Coelho-Junior HJ, Bucci C, Marzetti E. Circulating extracellular vesicles: friends and foes in neurodegeneration. Neural Regen Res. 2022; 17: 534-42.

[78] Chen Y, Zhao Y, Yin Y, Jia X, Mao L. Mechanism of cargo sorting into small extracellular vesicles. Bioengineered. 2021; 12: 8186-201.

[79] Lee YJ, Shin KJ, Chae YC. Regulation of cargo selection in exosome biogenesis and its biomedical applications in cancer. Exp Mol Med. 2024; 56: 877-89.

[80] Blanchette CR, Rodal AA. Mechanisms for biogenesis and release of neuronal extracellular vesicles. Curr Opin Neurobiol. 2020; 63: 104-10.

[81] Bloomingdale P, Karelina T, Ramakrishnan V, Bakshi S, Véronneau-Veilleux F, Moye M, et al. Hallmarks of neurodegenerative disease: A systems pharmacology perspective. CPT Pharmacometrics Syst Pharmacol. 2022; 11: 1399-429.

[82] Mosley RL, Gendelman HE. Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders. Exp Neurol. 2010; 222: 1-5.

[83] Zhang W, Xiao D, Mao Q, Xia H. Role of neuroinflammation in neurodegeneration development. Signal Transduct Target Ther. 2023; 8: 267.

[84] Cabrera-Pastor A. Extracellular Vesicles as Mediators of Neuroinflammation in Intercellular and Inter-Organ Crosstalk. Int J Mol Sci. 2024; 25: 7041.

[85] Marostica G, Gelibter S, Gironi M, Nigro A, Furlan R. Extracellular Vesicles in Neuroinflammation. Front Cell Dev Biol. 2021; 8: 623039.

[86] Ruan J, Miao X, Schlüter D, Lin L, Wang X. Extracellular vesicles in neuroinflammation: Pathogenesis, diagnosis, and therapy. Mol Ther. 2021; 29: 1946-57.

[87] Ahmad S, Srivastava RK, Singh P, Naik UP, Srivastava AK. Role of Extracellular Vesicles in Glia-Neuron Intercellular Communication. Front Mol Neurosci. 2022; 15: 844194.

[88] Paolicelli RC, Bergamini G, Rajendran L. Cell-to-cell Communication by Extracellular Vesicles: Focus on Microglia. Neuroscience. 2019; 405: 148-57.

[89] Qi H, Wang Y, Fa S, Yuan C, Yang L. Extracellular Vesicles as Natural Delivery Carriers Regulate Oxidative Stress Under Pathological Conditions. Front Bioeng Biotechnol. 2021; 9: 752019.

[90] Chiaradia E, Tancini B, Emiliani C, Delo F, Pellegrino RM, Tognoloni A, et al. Extracellular Vesicles under Oxidative Stress Conditions: Biological Properties and Physiological Roles. Cells. 2021; 10: 1763.

[91] Dayem AA, Yan E, Do M, Kim Y, Lee Y, Cho S, et al. Engineering extracellular vesicles for ROS scavenging and tissue regeneration. Nano Converg. 2024; 11: 24.

[92] Picca A, Guerra F, Calvani R, Coelho-Júnior HJ, Landi F, Bernabei R, et al. Extracellular Vesicles and Damage-Associated Molecular Patterns: A Pandora’s Box in Health and Disease. Front Immunol. 2020; 11: 601740.

[93] Busatto S, Morad G, Guo P, Moses MA. The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier. FASEB Bioadv. 2021; 3: 665-75.

[94] Hosseinkhani B, Duran G, Hoeks C, Hermans D, Schepers M, Baeten P, et al. Cerebral microvascular endothelial cell-derived extracellular vesicles regulate blood-brain barrier function. Fluids Barriers CNS. 2023; 20: 95.

[95] Sharma K, Zhang Y, Paudel KR, Kachelmeier A, Hansbro PM, Shi X. The Emerging Role of Pericyte-Derived Extracellular Vesicles in Vascular and Neurological Health. Cells. 2022; 11: 3108.

[96] Chen C, Chao Y, Lin H, Chen C, Chen C, Yang J, et al. miR-195 reduces age-related blood-brain barrier leakage caused by thrombospondin-1-mediated selective autophagy. Aging Cell. 2020; 19: e13236.

[97] Zhao S, Sheng S, Wang Y, Ding L, Xu X, Xia X, et al. Astrocyte-derived extracellular vesicles: A double-edged sword in central nervous system disorders. Neurosci Biobehav Rev. 2021; 125: 148-59.

[98] Fayazi N, Sheykhhasan M, Asl SS, Najafi R. Stem Cell-Derived Exosomes: a New Strategy of Neurodegenerative Disease Treatment. Mol Neurobiol. 2021; 58: 3494-514.

[99] Zhong L, Wang J, Wang P, Liu X, Liu P, Cheng X, et al. Neural stem cell-derived exosomes and regeneration: cell-free therapeutic strategies for traumatic brain injury. Stem Cell Res Ther. 2023; 14: 198.

[100] Salikhova DI, Timofeeva AV, Golovicheva VV, Fatkhudinov TK, Shevtsova YA, Soboleva AG, et al. Extracellular vesicles of human glial cells exert neuroprotective effects via brain miRNA modulation in a rat model of traumatic brain injury. Sci Rep. 2023; 13: 20388.

[101] Campero-Romero AN, Real FH, Santana-Martínez RA, Molina-Villa T, Aranda C, Ríos-Castro E, et al. Extracellular vesicles from neural progenitor cells promote functional recovery after stroke in mice with pharmacological inhibition of neurogenesis. Cell Death Discov. 2023; 9: 272.

[102] Wiklander OPB, Brennan MÁ, Lötvall J, Breakefield XO, El Andaloussi S. Advances in therapeutic applications of extracellular vesicles. Sci Transl Med. 2019; 11: eaav8521.

[103] Klyachko NL, Arzt CJ, Li SM, Gololobova OA, Batrakova EV. Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations. Pharmaceutics. 2020; 12: 1171.

[104] Hu G, Liao K, Niu F, Yang L, Dallon BW, Callen S, et al. Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration. Mol Ther Nucleic Acids. 2018; 13: 450-63.

[105] Liao K, Niu F, Dagur RS, He M, Tian C, Hu G. Intranasal Delivery of lincRNA-Cox2 siRNA Loaded Extracellular Vesicles Decreases Lipopolysaccharide-Induced Microglial Proliferation in Mice. J Neuroimmune Pharmacol. 2020; 15: 390-9.

[106] Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011; 29: 341-5.

[107] Xie H, Lei N, Gong A, Chen X, Hu G. Cryptosporidium parvum induces SIRT1 expression in host epithelial cells through downregulating let-7i. Hum Immunol. 2014; 75: 760-5.

[108] Lu Z, Shen J, Yang J, Wang J, Zhao R, Zhang T, et al. Nucleic acid drug vectors for diagnosis and treatment of brain diseases. Signal Transduct Target Ther. 2023; 8: 39.

[109] Jahangard Y, Monfared H, Moradi A, Zare M, Mirnajafi-Zadeh J, Mowla SJ. Therapeutic Effects of Transplanted Exosomes Containing miR-29b to a Rat Model of Alzheimer’s Disease. Front Neurosci. 2020; 14: 564.

[110] Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012; 30: 1556-64.

[111] Yu Y, Gibbs KM, Davila J, Campbell N, Sung S, Todorova TI, et al. MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish. Eur J Neurosci. 2011; 33: 1587-97.

[112] Lim WQ, Luk KHM, Lee KY, Nurul N, Loh SJ, Yeow ZX, et al. Small Extracellular Vesicles’ miRNAs: Biomarkers and Therapeutics for Neurodegenerative Diseases. Pharmaceutics. 2023; 15: 1216.

[113] Oliveira JT, Yanick C, Wein N, Limia CEG. Neuron-Schwann cell interactions in peripheral nervous system homeostasis, disease, and preclinical treatment. Front Cell Neurosci. 2023; 17: 1248922.

[114] Liang Y, Iqbal Z, Lu J, Wang J, Zhang H, Chen X, et al. Cell-derived nanovesicle-mediated drug delivery to the brain: Principles and strategies for vesicle engineering. Mol Ther. 2023; 31: 1207-24.

[115] Yuan Q, Li XD, Zhang SM, Wang HW, Wang YL. Extracellular vesicles in neurodegenerative diseases: Insights and new perspectives. Genes Dis. 2019; 8: 124-32.

[116] Zheng X, Sun K, Liu Y, Yin X, Zhu H, Yu F, et al. Resveratrol-loaded macrophage exosomes alleviate multiple sclerosis through targeting microglia. J Control Release. 2023; 353: 675-84.

[117] Song C, Xu S, Chang L, Zhao X, Mei X, Ren X, et al. Preparation of EGCG decorated, injectable extracellular vesicles for cartilage repair in rat arthritis. Regen Biomater. 2021; 8: rbab067.

[118] Aparicio-Trejo OE, Aranda-Rivera AK, Osorio-Alonso H, Martínez-Klimova E, Sánchez-Lozada LG, Pedraza-Chaverri J, et al. Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease. Antioxidants (Basel). 2022; 11: 356.

[119] Teleanu DM, Niculescu A, Lungu II, Radu CI, Vladâcenco O, Roza E, et al. An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases. Int J Mol Sci. 2022; 23: 5938.

[120] Yang J, Wu S, Hou L, Zhu D, Yin S, Yang G, et al. Therapeutic Effects of Simultaneous Delivery of Nerve Growth Factor mRNA and Protein via Exosomes on Cerebral Ischemia. Mol Ther Nucleic Acids. 2020; 21: 512-22.

[121] Tan F, Li X, Wang Z, Li J, Shahzad K, Zheng J. Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther. 2024; 9: 17.

[122] Dong Z, Gu H, Guo Q, Liu X, Li F, Liu H, et al. Circulating Small Extracellular Vesicle-Derived miR-342-5p Ameliorates Beta-Amyloid Formation via Targeting Beta-site APP Cleaving Enzyme 1 in Alzheimer’s Disease. Cells. 2022; 11: 3830.

[123] Zhu Y, Huang R, Wang D, Yu L, Liu Y, Huang R, et al. EVs-mediated delivery of CB2 receptor agonist for Alzheimer’s disease therapy. Asian J Pharm Sci. 2023; 18: 100835.

[124] Wang S, Jia J, Wang Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppresses iNOS Expression and Ameliorates Neural Impairment in Alzheimer’s Disease Mice. J Alzheimers Dis. 2018; 61: 1005-13.

[125] Ma X, Huang M, Zheng M, Dai C, Song Q, Zhang Q, et al. ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer’s disease. J Control Release. 2020; 327: 688-702.

[126] Lin L, Huang L, Huang S, Chen W, Huang H, Chi L, et al. MSC-Derived Extracellular Vesicles Alleviate NLRP3/GSDMD-Mediated Neuroinflammation in Mouse Model of Sporadic Alzheimer’s Disease. Mol Neurobiol. 2024; 61: 5494-509.

[127] Li B, Chen Y, Zhou Y, Feng X, Gu G, Han S, et al. Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer’s disease. Neural Regen Res. 2024; 19: 1593-601.

[128] Attaluri S, Gonzalez JJ, Kirmani M, Vogel AD, Upadhya R, Kodali M, et al. Intranasally administered extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells quickly incorporate into neurons and microglia in 5xFAD mice. Front Aging Neurosci. 2023; 15: 1200445.

[129] Zhang C, Shao W, Yuan H, Xiao R, Zhang Y, Wei C, et al. Engineered Extracellular Vesicle-Based Nanoformulations That Coordinate Neuroinflammation and Immune Homeostasis, Enhancing Parkinson’s Disease Therapy. ACS Nano. 2024; 18: 23014-31.

[130] He Y, Li R, Yu Y, Xu Z, Gao J, Wang C, et al. HucMSC extracellular vesicles increasing SATB 1 to activate the Wnt/β-catenin pathway in 6-OHDA-induced Parkinson’s disease model. IUBMB Life. 2024; 76: 1154-74.

[131] Esteves M, Abreu R, Fernandes H, Serra-Almeida C, Martins PAT, Barão M, et al. MicroRNA-124-3p-enriched small extracellular vesicles as a therapeutic approach for Parkinson’s disease. Mol Ther. 2022; 30: 3176-92.

[132] Lee EJ, Choi Y, Lee HJ, Hwang DW, Lee DS. Human neural stem cell-derived extracellular vesicles protect against Parkinson’s disease pathologies. J Nanobiotechnology. 2022; 20: 198.

[133] Lee M, Im W, Kim M. Exosomes as a potential messenger unit during heterochronic parabiosis for amelioration of Huntington’s disease. Neurobiol Dis. 2021; 155: 105374.

[134] Bahar R, Darabi S, Norouzian M, Roustaei S, Torkamani-Dordshaikh S, Hasanzadeh M, et al. Neuroprotective effect of human cord blood-derived extracellular vesicles by improved neuromuscular function and reduced gliosis in a rat model of Huntington’s disease. J Chem Neuroanat. 2024; 138: 102419.

[135] Joshi BS, Youssef SA, Bron R, de Bruin A, Kampinga HH, Zuhorn IS. DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease. iScience. 2021; 24: 103282.

[136] Beatriz M, Rodrigues RJ, Vilaça R, Egas C, Pinheiro PS, Daley GQ, et al. Extracellular vesicles improve GABAergic transmission in Huntington’s disease iPSC-derived neurons. Theranostics. 2023; 13: 3707-24.

[137] Gschwendtberger T, Thau-Habermann N, von der Ohe J, Luo T, Hass R, Petri S. Protective effects of EVs/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons. Neurosci Lett. 2023; 816: 137493.

[138] Bonafede R, Turano E, Scambi I, Busato A, Bontempi P, Virla F, et al. ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS. Int J Mol Sci. 2020; 21: 3651.

[139] Lee M, Ban J, Kim KY, Jeon GS, Im W, Sung J, et al. Adipose-derived stem cell exosomes alleviate pathology of amyotrophic lateral sclerosis in vitro. Biochem Biophys Res Commun. 2016; 479: 434-9.

[140] Thome AD, Thonhoff JR, Zhao W, Faridar A, Wang J, Beers DR, et al. Extracellular Vesicles Derived From Ex Vivo Expanded Regulatory T Cells Modulate In Vitro and In Vivo Inflammation. Front Immunol. 2022; 13: 875825.

[141] Santos SIP, Ortiz-Peñuela SJ, de Paula Filho A, Tomiyama ALMR, Coser LO, da Silveira JC, et al. Oligodendrocyte precursor cell-derived exosomes combined with cell therapy promote clinical recovery by immunomodulation and gliosis attenuation. Front Cell Neurosci. 2024; 18: 1413843.

[142] Manni G, Gargaro M, Ricciuti D, Fontana S, Padiglioni E, Cipolloni M, et al. Amniotic fluid stem cell-derived extracellular vesicles educate type 2 conventional dendritic cells to rescue autoimmune disorders in a multiple sclerosis mouse model. J Extracell Vesicles. 2024; 13: e12446.

[143] Shi Z, Sun H, Tian X, Song X, Fan J, Sun S, et al. Extracellular vesicles containing miR-181a-5p as a novel therapy for experimental autoimmune encephalomyelitis-induced demyelination. Int Immunopharmacol. 2024; 135: 112326.

[144] Turano E, Scambi I, Bonafede R, Dusi S, Angelini G, Lopez N, et al. Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis. Cytotherapy. 2024; 26: 276-85.

[145] Krishnan MA, Alimi OA, Pan T, Kuss M, Korade Z, Hu G, et al. Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System. Pharmaceutics. 2024; 16: 102.

[146] Yu X, Bai Y, Han B, Ju M, Tang T, Shen L, et al. Extracellular vesicle-mediated delivery of circDYM alleviates CUS-induced depressive-like behaviours. J Extracell Vesicles. 2022; 11: e12185.

[147] Chivero ET, Liao K, Niu F, Tripathi A, Tian C, Buch S, et al. Engineered Extracellular Vesicles Loaded With miR-124 Attenuate Cocaine-Mediated Activation of Microglia. Front Cell Dev Biol. 2020; 8: 573.

[148] Hwang HS, Kim H, Han G, Lee JW, Kim K, Kwon IC, et al. Extracellular Vesicles as Potential Therapeutics for Inflammatory Diseases. Int J Mol Sci. 2021; 22: 5487.

[149] Ma R, Chen L, Hu G. Extracellular Vesicles: Therapeutic Delivery. Neuroimmune Pharmacology and Therapeutics. Cham: Springer; 2024. pp. 855-71. [DOI]

[150] Salunkhe S, Dheeraj, Basak M, Chitkara D, Mittal A. Surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: Strategies and significance. J Control Release. 2020; 326: 599-614.

[151] Cui G, Guo H, Li H, Zhai Y, Gong Z, Wu J, et al. RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease. Immun Ageing. 2019; 16: 10.

[152] Yu Y, Li W, Mao L, Peng W, Long D, Li D, et al. Genetically engineered exosomes display RVG peptide and selectively enrich a neprilysin variant: a potential formulation for the treatment of Alzheimer’s disease. J Drug Target. 2021; 29: 1128-38.

[153] Walker S, Busatto S, Pham A, Tian M, Suh A, Carson K, et al. Extracellular vesicle-based drug delivery systems for cancer treatment. Theranostics. 2019; 9: 8001-17.

[154] Sato YT, Umezaki K, Sawada S, Mukai S, Sasaki Y, Harada N, et al. Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep. 2016; 6: 21933.

[155] Hu G, Brew BJ. Extracellular vesicle small noncoding RNAs: a window into pathogenesis and diagnosis. AIDS. 2023; 37: 849-50.