Table Info

Table 1.

Preclinical studies of EVs as delivery vehicles in neurodegenerative disorders

Disease	EV source or cargo	Animal models	Effects	References
Alzheimer’s disease	Mesenchymal stem cells (MSCs)-derived EVs	APP/PS1 and icv-STZ mice	Alleviate Aβ-induced iNOS and inflammation	[124, 126]
	Adipose-derived mesenchymal stem cells (ADSCs)-derived EVs	APP/PS1 mice	Reduce Aβ deposition and decrease microglia activation	[125]
	Neural stem cell-derived exosomes	APP/PS1 and 5xFAD mice	Promote mitochondrial biogenesis and restore abnormal protein distribution	[127, 128]
	EVs-mediated delivery of CB2 receptor agonist	APP/PS1 mice	Enhance neuronal regeneration	[123]
Parkinson’s disease	CCR2-enriched mesenchymal stem cell-derived EVs (MSCCCR2-EVs)	MPTP-induced PD mice	Block the infiltration of peripheral inflammatory cells	[129]
	Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-EVs)	6-OHDA-induced PD mice	Activate the Wnt/β-catenin pathway and reduce autophagy	[130]
	Human umbilical cord blood-derived mononuclear cells (hUCB-MNCs) enriched with miR-124-3p (miR-124-3p sEVs)	6-OHDA-induced PD mice	Induce neuronal differentiation and protect N27 dopaminergic cells	[131]
	Human neural stem cell-derived EVs	6-OHDA-induced PD mice	Reduce intracellular reactive oxygen species (ROS) and associated apoptotic pathways	[132]
Huntington’s disease	Young serum-exosomes	R6/2 mice model	Reduce mHTT aggregation protein and apoptotic signaling	[133]
	Human cord blood-derived EVs	3-NP-induced HD rats	Reduce neuroinflammation	[134]
	DNAJB6b-enriched neural stem cells (NSCs)-derived EVs	R6/2 mice model	Reduce mHTT aggregation	[135]
	Fibroblast-derived EVs	HD-derived neuron cultures	Increase the density of inhibitory synapses	[136]
Amyotrophic lateral sclerosis	Mesenchymal stroma-/stem-like cells-derived EVs	SOD1(G93A) transgenic primary motor neurons	Antioxidant and anti-apoptotic pathways	[137]
	Adipose-derived stem cell-derived exosomes (ASC-exosomes)	SOD1(G93A) mice	Improve motor performance; protect lumbar motoneurons; and decrease glial activation	[138]
	Adipose-derived stem cell exosomes	Neuronal cells from G93A ALS mice	Reduce cytosolic SOD1 level	[139]
	Regulatory T cell-derived EVs	SOD1 mice	Increase survival, and modulate inflammation	[140]
Multiple sclerosis	Oligodendrocyte precursor cell-derived exosomes	Experimental autoimmune encephalomyelitis (EAE) mice	Reduce microgliosis and astrogliosis	[141]
	Amniotic fluid stem cell-derived EVs	EAE mice	Reprogramming inflammatory cDC2s	[142]
	Mesenchymal stem cell-derived EVs containing miR-181a-5p	EAE mice	Inhibit microglial inflammation and pyroptosis through the USP15-mediated RelA/NEK7 axis	[143]
	Adipose mesenchymal stem cell-derived EVs	EAE mice	Target inflamed lymph nodes	[144]

Declarations

Acknowledgments

During the preparation of this review article, the authors utilized ChatGPT-4 and DeepSeek-V3 for language editing and refinement. After employing these tools, the authors carefully reviewed, revised, and edited the content as necessary. The authors take full responsibility for the final content and accuracy of the publication.

Author contributions

NH: Writing—original draft, Writing—review & editing. LC: Visualization, Writing—review & editing. GH: Conceptualization, Writing—review & editing. RM: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Supervision. All authors have read and approved the final submitted version of the manuscript.

Conflicts of interest

Guoku Hu is the Editorial Board Member and a Guest Editor of Exploration of Neuroprotective Therapy, and Rong Ma is a Guest Editor of Exploration of Neuroprotective Therapy. However, neither was involved in the decision-making or review process for this manuscript. The other authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

LC acknowledges the support of the National Natural Science Foundation of China [62002212] and 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant [2020LKSFG07D]. GH was supported by startup funds from University of Nebraska Medical Center and the National Institutes of Health (NIH) grants [DA046831], [DA042704], and [DA043138], [MH112848]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

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

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

Saudou F, Humbert S. The Biology of Huntingtin. Neuron. 2016;89:910–26. [DOI] [PubMed]

Masrori P, Damme PV. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27:1918–29. [DOI] [PubMed] [PMC]

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

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

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

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

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

15.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

20.

Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019;88:487–514. [DOI] [PubMed]

21.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

24.

Buzas EI. The roles of extracellular vesicles in the immune system. Nat Rev Immunol. 2023;23:236–50. [DOI] [PubMed] [PMC]

25.

Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83. [DOI] [PubMed] [PMC]

26.

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

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. [DOI] [PubMed] [PMC]

28.

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

29.

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

30.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

34.

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

35.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

38.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

41.

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

42.

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

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. [DOI] [PubMed] [PMC]

44.

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

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

50.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

53.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

60.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

63.

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

64.

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

65.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

70.

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

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. [DOI] [PubMed] [PMC]

72.

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

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. [DOI] [PubMed] [PMC]

74.

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

75.

Howitt J, Hill AF. Exosomes in the Pathology of Neurodegenerative Diseases. J Biol Chem. 2016;291:26589–97. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

78.

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

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. [DOI] [PubMed] [PMC]

80.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

83.

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

84.

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

85.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

88.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

103.

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

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed]

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. [DOI] [PubMed] [PMC]

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. [DOI] [PubMed] [PMC]

155.

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