Exploration of Neuroscience

Table 2. Studies utilizing modified EVs on PD models

Therapeutic cargo	EV source (cell line or biofluid)	Modification	Loading method	Ref.
α-Syn siRNA	Dendritic cell	Lamp2b-RVG	Electroporation	[98]
Catalase	RAW 264.7	Unmodified	Co-incubation, saponin permeabilization, freeze-thaw cycles, sonication, and extrusion	[87]
Catalase mRNA	HEK293T	Lamp2b-RVG	n/a	[101]
DA	Blood	Transferrin pretreatment	Co-incubation	[97]
Anti-α-Syn shRNA-MCs	Dendritic cell	Lamp2b-RVG	Electroporation	[102]
Aptamer F5R1 and F5R2	HEK293T	Lamp2b-RVG	Co-incubation	[100]
Natural EV-cargo with curcumin	MSCs	SA-P and SA-RVG	Sonication	[91]

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n/a: not applicable; shRNA-MCs: short hairpin RNA minicircles

Declarations

Acknowledgments

The authors acknowledge Servier Medical Art (https://smart.servier.com) and BioIcons (https://bioicons.com) for providing the icons used for the images. Icons were developed by Servier and DBCLS and licensed under Creative Commons Attribution 3.0 Unported License and Creative Commons Attribution 4.0 International License, respectively.

Author contributions

MRT and ALA equally contributed to: Conceptualization, Writing—original draft, Visualization. VRdC and JRDP: Writing—original draft. RPA: Supervision, Writing—review & editing.

Conflicts of interest

The 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

Not applicable.

Copyright

References

Balestrino R, Schapira AHV. Parkinson disease. Eur J Neurol. 2020;27:27–42. [DOI] [PubMed]

Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. [DOI] [PubMed]

Zambrano K, Barba D, Castillo K, Noboa L, Argueta-Zamora D, Robayo P, et al. Fighting Parkinson’s disease: the return of the mitochondria. Mitochondrion. 2022;64:34–44. [DOI] [PubMed]

Zafar S, Yaddanapudi SS. Parkinson disease. Treasure Island (FL): StatPearls Publishing; 2022.

de Lau LML, Breteler MMB. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–35. [DOI] [PubMed]

Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397:2284–303. [DOI] [PubMed]

Budnik V, Ruiz-Cañada C, Wendler F. Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci. 2016;17:160–72. [DOI] [PubMed] [PMC]

Deus CM, Tavares H, Beatriz M, Mota S, Lopes C. Mitochondrial damage-associated molecular patterns content in extracellular vesicles promotes early inflammation in neurodegenerative disorders. Cells. 2022;11:2364. [DOI] [PubMed] [PMC]

Araldi RP, D’Amelio F, Vigerelli H, de Melo TC, Kerkis I. Stem cell-derived exosomes as therapeutic approach for neurodegenerative disorders: from biology to biotechnology. Cells. 2020;9:2663. [DOI] [PubMed] [PMC]

10.

Porro C, Panaro MA, Lofrumento DD, Hasalla E, Trotta T. The multiple roles of exosomes in Parkinson’s disease: an overview. Immunopharmacol Immunotoxicol. 2019;41:469–76. [DOI] [PubMed]

11.

Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177:428–45.e18. [DOI] [PubMed] [PMC]

12.

Kodali M, Castro OW, Kim DK, Thomas A, Shuai B, Attaluri S, et al. Intranasally administered human MSC-derived extracellular vesicles pervasively incorporate into neurons and microglia in both intact and status epilepticus injured forebrain. Int J Mol Sci. 2020;21:181. [DOI] [PubMed] [PMC]

13.

Manickam DS. Delivery of mitochondria via extracellular vesicles – a new horizon in drug delivery. J Control Release. 2022;343:400–7. [DOI] [PubMed]

14.

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]

15.

Xu M, Feng T, Liu B, Qiu F, Xu Y, Zhao Y, et al. Engineered exosomes: desirable target-tracking characteristics for cerebrovascular and neurodegenerative disease therapies. Theranostics. 2021;11:8926–44. [DOI] [PubMed] [PMC]

16.

Reed X, Bandrés-Ciga S, Blauwendraat C, Cookson MR. The role of monogenic genes in idiopathic Parkinson’s disease. Neurobiol Dis. 2019;124:230–9. [DOI] [PubMed] [PMC]

17.

Yang W, Hamilton JL, Kopil C, Beck JC, Tanner CM, Albin RL, et al. Current and projected future economic burden of Parkinson’s disease in the U.S. NPJ Parkinsons Dis. 2020;6:15. [DOI] [PubMed] [PMC]

18.

Borsche M, Pereira SL, Klein C, Grünewald A. Mitochondria and Parkinson’s disease: clinical, molecular, and translational aspects. J Parkinsons Dis. 2021;11:45–60. [DOI] [PubMed] [PMC]

19.

GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease study 2016. Lancet Neurol. 2019;18:459–80. [DOI] [PubMed] [PMC]

20.

de Araújo FM, Cuenca-Bermejo L, Fernández-Villalba E, Costa SL, Silva VDA, Herrero MT. Role of microgliosis and NLRP3 inflammasome in Parkinson’s disease pathogenesis and therapy. Cell Mol Neurobiol. 2022;42:1283–300. [DOI] [PubMed]

21.

Drui G, Carnicella S, Carcenac C, Favier M, Bertrand A, Boulet S, et al. Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson’s disease. Mol Psychiatry. 2014;19:358–67. [DOI] [PubMed] [PMC]

22.

Hindle JV. Ageing, neurodegeneration and Parkinson’s disease. Age Ageing. 2010;39:156–61. [DOI] [PubMed]

23.

González-Rodríguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature. 2021;599:650–6. Erratum in: Nature. 2022;603:E1. [DOI] [PubMed] [PMC]

24.

Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017;155:96–119. [DOI] [PubMed] [PMC]

25.

Nakamura K, Nemani VM, Wallender EK, Kaehlcke K, Ott M, Edwards RH. Optical reporters for the conformation of α-synuclein reveal a specific interaction with mitochondria. J Neurosci. 2008;28:12305–17. [DOI] [PubMed] [PMC]

26.

Peterson LJ, Flood PM. Oxidative stress and microglial cells in Parkinson’s disease. Mediators Inflamm. 2012;2012:401264. [DOI] [PubMed] [PMC]

27.

Farmen K, Tofiño-Vian M, Iovino F. Neuronal damage and neuroinflammation, a bridge between bacterial meningitis and neurodegenerative diseases. Front Cell Neurosci. 2021;15:680858. [DOI] [PubMed] [PMC]

28.

Grotemeyer A, McFleder RL, Wu J, Wischhusen J, Ip CW. Neuroinflammation in Parkinson’s disease – putative pathomechanisms and targets for disease-modification. Front Immunol. 2022;13:878771. [DOI] [PubMed] [PMC]

29.

Weintraub D, Doshi J, Koka D, Davatzikos C, Siderowf AD, Duda JE, et al. Neurodegeneration across stages of cognitive decline in Parkinson disease. Arch Neurol. 2011;68:1562–8. [DOI] [PubMed] [PMC]

30.

Shahmoradian SH, Lewis AJ, Genoud C, Hench J, Moors TE, Navarro PP, et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat Neurosci. 2019;22:1099–109. [DOI] [PubMed]

31.

Chen C, Turnbull DM, Reeve AK. Mitochondrial dysfunction in Parkinson’s disease—cause or consequence? Biology (Basel). 2019;8:38. [DOI] [PubMed] [PMC]

32.

Vilaça-Faria H, Salgado AJ, Teixeira FG. Mesenchymal stem cells-derived exosomes: a new possible therapeutic strategy for Parkinson’s disease? Cells. 2019;8:118. [DOI] [PubMed] [PMC]

33.

Malpartida AB, Williamson M, Narendra DP, Wade-Martins R, Ryan BJ. Mitochondrial dysfunction and mitophagy in Parkinson’s disease: from mechanism to therapy. Trends Biochem Sci. 2021;46:329–43. [DOI] [PubMed]

34.

Dernie F. Mitophagy in Parkinson’s disease: from pathogenesis to treatment target. Neurochem Int. 2020;138:104756. [DOI] [PubMed]

35.

Picca A, Guerra F, Calvani R, Bucci C, Lo Monaco MR, Bentivoglio AR, et al. Mitochondrial dysfunction and aging: insights from the analysis of extracellular vesicles. Int J Mol Sci. 2019;20:805. [DOI] [PubMed] [PMC]

36.

Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013;106-107:17–32. [DOI] [PubMed] [PMC]

37.

Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol. 2019;15:565–81. [DOI] [PubMed]

38.

Lemoine M. The evolution of the hallmarks of aging. Front Genet. 2021;12:693071. [DOI] [PubMed] [PMC]

39.

Amo T, Sato S, Saiki S, Wolf AM, Toyomizu M, Gautier CA, et al. Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects. Neurobiol Dis. 2011;41:111–8. [DOI] [PubMed]

40.

Picca A, Guerra F, Calvani R, Romano R, Coelho-Júnior HJ, Bucci C, et al. Mitochondrial dysfunction, protein misfolding and neuroinflammation in Parkinson’s disease: roads to biomarker discovery. Biomolecules. 2021;11:1508. [DOI] [PubMed] [PMC]

41.

Haddad D, Nakamura K. Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson’s disease. FEBS Lett. 2015;589:3702–13. [DOI] [PubMed] [PMC]

42.

Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 2012;31:3038–62. [DOI] [PubMed] [PMC]

43.

Bido S, Muggeo S, Massimino L, Marzi MJ, Giannelli SG, Melacini E, et al. Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity. Nat Commun. 2021;12:6237. Erratum in: Nat Commun. 2021;12:7359. [DOI] [PubMed] [PMC]

44.

Kong SM, Chan BK, Park JS, Hill KJ, Aitken JB, Cottle L, et al. Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-synuclein externalization via exosomes. Hum Mol Genet. 2014;23:2816–33. [DOI] [PubMed]

45.

Li KL, Huang HY, Ren H, Yang XL. Role of exosomes in the pathogenesis of inflammation in Parkinson’s disease. Neural Regen Res. 2022;17:1898–906. [DOI] [PubMed] [PMC]

46.

Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750. [DOI] [PubMed] [PMC]

47.

van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28. [DOI] [PubMed]

48.

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]

49.

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]

50.

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]

51.

Thompson AG, Gray E, Heman-Ackah SM, Mäger I, Talbot K, Andaloussi SE, et al. Extracellular vesicles in neurodegenerative disease — pathogenesis to biomarkers. Nat Rev Neurol. 2016;12:346–57. [DOI] [PubMed]

52.

van der Pol E, Böing AN, Gool EL, Nieuwland R. Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles. J Thromb Haemost. 2016;14:48–56. Erratum in: J Thromb Haemost. 2016;14:2087. [DOI] [PubMed]

53.

Margolis L, Sadovsky Y. The biology of extracellular vesicles: the known unknowns. PLoS Biol. 2019;17:e3000363. [DOI] [PubMed] [PMC]

54.

Vader P, Mol EA, Pasterkamp G, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev. 2016;106:148–56. [DOI] [PubMed]

55.

Upadhya R, Shetty AK. Extracellular vesicles for the diagnosis and treatment of Parkinson’s disease. Aging Dis. 2021;12:1438–50. [DOI] [PubMed] [PMC]

56.

Wu X, Zheng T, Zhang B. Exosomes in Parkinson’s disease. Neurosci Bull. 2017;33:331–8. [DOI] [PubMed] [PMC]

57.

Cao Z, Wu Y, Liu G, Jiang Y, Wang X, Wang Z, et al. α-Synuclein in salivary extracellular vesicles as a potential biomarker of Parkinson’s disease. Neurosci Lett. 2019;696:114–20. [DOI] [PubMed]

58.

Chung CC, Chan L, Chen JH, Hung YC, Hong CT. Plasma extracellular vesicle α-synuclein level in patients with Parkinson’s disease. Biomolecules. 2021;11:744. [DOI] [PubMed] [PMC]

59.

Lazo S, Noren Hooten N, Green J, Eitan E, Mode NA, Liu QR, et al. Mitochondrial DNA in extracellular vesicles declines with age. Aging Cell. 2021;20:e13283. [DOI] [PubMed] [PMC]

60.

Tofaris GK. A critical assessment of exosomes in the pathogenesis and stratification of Parkinson’s disease. J Parkinsons Dis. 2017;7:569–76. [DOI] [PubMed] [PMC]

61.

Hill AF. Extracellular vesicles and neurodegenerative diseases. J Neurosci. 2019;39:9269–73. [DOI] [PubMed] [PMC]

62.

Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113:E968–77. [DOI] [PubMed] [PMC]

63.

Marchetti B, Leggio L, L’Episcopo F, Vivarelli S, Tirolo C, Paternò G, et al. Glia-derived extracellular vesicles in Parkinson’s disease. J Clin Med. 2020;9:1941. [DOI] [PubMed] [PMC]

64.

Morishita M, Takahashi Y, Nishikawa M, Takakura Y. Pharmacokinetics of exosomes—an important factor for elucidating the biological roles of exosomes and for the development of exosome-based therapeutics. J Pharm Sci. 2017;106:2265–9. [DOI] [PubMed]

65.

Pascual M, Ibáñez F, Guerri C. Exosomes as mediators of neuron-glia communication in neuroinflammation. Neural Regen Res. 2020;15:796–801. [DOI] [PubMed] [PMC]

66.

Almeria C, Kreß S, Weber V, Egger D, Kasper C. Heterogeneity of mesenchymal stem cell-derived extracellular vesicles is highly impacted by the tissue/cell source and culture conditions. Cell Biosci. 2022;12:51. [DOI] [PubMed] [PMC]

67.

Leggio L, Paternò G, Vivarelli S, L’Episcopo F, Tirolo C, Raciti G, et al. Extracellular vesicles as nanotherapeutics for Parkinson’s disease. Biomolecules. 2020;10:1327. [DOI] [PubMed] [PMC]

68.

Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther. 2018;9:63. [DOI] [PubMed] [PMC]

69.

Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther. 2015;23:812–23. [DOI] [PubMed] [PMC]

70.

Bai X, Dong Q, Zhao L, Yao Y, Wang B. microRNA-106b-containing extracellular vesicles affect autophagy of neurons by regulating CDKN2B in Parkinson’s disease. Neurosci Lett. 2021;760:136094. [DOI] [PubMed]

71.

Chen HX, Liang FC, Gu P, Xu BL, Xu HJ, Wang WT, et al. Exosomes derived from mesenchymal stem cells repair a Parkinson’s disease model by inducing autophagy. Cell Death Dis. 2020;11:288. [DOI] [PubMed] [PMC]

72.

Chen WS, Lin TY, Kuo CH, Hsieh DJ, Kuo WW, Liao SC, et al. Ginkgolide A improves the pleiotropic function and reinforces the neuroprotective effects by mesenchymal stem cell-derived exosomes in 6-OHDA-induced cell model of Parkinson’s disease. Aging (Albany NY). 2023;15:1358–70. [DOI] [PubMed] [PMC]

73.

Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–8. Erratum in: Stem Cells. 2017;35:2103. [DOI] [PubMed]

74.

Jarmalavičiūtė A, Tunaitis V, Pivoraitė U, Venalis A, Pivoriūnas A. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis. Cytotherapy. 2015;17:932–9. [DOI] [PubMed]

75.

Narbute K, Piļipenko V, Pupure J, Dzirkale Z, Jonavičė U, Tunaitis V, et al. Intranasal administration of extracellular vesicles derived from human teeth stem cells improves motor symptoms and normalizes tyrosine hydroxylase expression in the substantia nigra and striatum of the 6-hydroxydopamine-treated rats. Stem Cells Transl Med. 2019;8:490–9. [DOI] [PubMed] [PMC]

76.

Zhang ZX, Zhou YJ, Gu P, Zhao W, Chen HX, Wu RY, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson’s disease and neuronal damage through inhibition of microglia. Neural Regen Res. 2023;18:2291–300. [DOI] [PubMed]

77.

Li Y, Li Z, Gu J, Xu X, Chen H, Gui Y. Exosomes isolated during dopaminergic neuron differentiation suppressed neuronal inflammation in a rodent model of Parkinson’s disease. Neurosci Lett. 2022;771:136414. [DOI] [PubMed]

78.

Li Z, Li Y, Xu X, Gu J, Chen H, Gui Y. Exosomes rich in Wnt5 improved circadian rhythm dysfunction via enhanced PPARγ activity in the 6-hydroxydopamine model of Parkinson’s disease. Neurosci Lett. 2023;802:137139. [DOI] [PubMed]

79.

Samir M, Ibrahim NE, Medhat E, El-Din SS, Abdel-Rahman M, Ahmed AA. Combined mesenchymal stem cell-derived exosomes and H2S ameliorated the neurodegenerative changes in Parkinson’s disease: implication of PI3K/AKT signaling pathway. Egypt Acad J Biolog Sci (C. Physiology and Molecular biology). 2022;14:203–23.

80.

Martin I, Galipeau J, Kessler C, Le Blanc K, Dazzi F. Challenges for mesenchymal stromal cell therapies. Sci Transl Med. 2019;11:eaat2189. [DOI] [PubMed]

81.

Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17:11–22. [DOI] [PubMed]

82.

Yang Z, Shi J, Xie J, Wang Y, Sun J, Liu T, et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat Biomed Eng. 2020;4:69–83. Erratum in: Nat Biomed Eng. 2021;5:944–5. [DOI] [PubMed] [PMC]

83.

Armstrong JPK, Stevens MM. Strategic design of extracellular vesicle drug delivery systems. Adv Drug Deliv Rev. 2018;130:12–6. [DOI] [PubMed] [PMC]

84.

Liu C, Su C. Design strategies and application progress of therapeutic exosomes. Theranostics. 2019;9:1015–28. [DOI] [PubMed] [PMC]

85.

Alvarez-Erviti L, Couch Y, Richardson J, Cooper JM, Wood MJ. Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci Res. 2011;69:337–42. [DOI] [PubMed]

86.

Hall J, Prabhakar S, Balaj L, Lai CP, Cerione RA, Breakefield XO. Delivery of therapeutic proteins via extracellular vesicles: review and potential treatments for Parkinson’s disease, glioma, and schwannoma. Cell Mol Neurobiol. 2016;36:417–27. [DOI] [PubMed] [PMC]

87.

Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18–30. Erratum in: J Control Release. 2021;339:232–4. [DOI] [PubMed] [PMC]

88.

Fu S, Wang Y, Xia X, Zheng JC. Exosome engineering: current progress in cargo loading and targeted delivery. NanoImpact. 2020;20:100261. [DOI]

89.

Murphy DE, de Jong OG, Brouwer M, Wood MJ, Lavieu G, Schiffelers RM, et al. Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking. Exp Mol Med. 2019;51:1–12. [DOI] [PubMed] [PMC]

90.

Salunkhe S, DheerajBasak 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]

91.

Peng H, Li Y, Ji W, Zhao R, Lu Z, Shen J, et al. Intranasal administration of self-oriented nanocarriers based on therapeutic exosomes for synergistic treatment of Parkinson’s disease. ACS Nano. 2022;16:869–84. [DOI] [PubMed]

92.

Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol. 2007;595:453–70. [DOI] [PubMed]

93.

Singh PK, Kotia V, Ghosh D, Mohite GM, Kumar A, Maji SK. Curcumin modulates α-synuclein aggregation and toxicity. ACS Chem Neurosci. 2013;4:393–407. [DOI] [PubMed] [PMC]

94.

Loch-Neckel G, Matos AT, Vaz AR, Brites D. Challenges in the development of drug delivery systems based on small extracellular vesicles for therapy of brain diseases. Front Pharmacol. 2022;13:839790. [DOI] [PubMed] [PMC]

95.

Ye Z, Zhang T, He W, Jin H, Liu C, Yang Z, et al. Methotrexate-loaded extracellular vesicles functionalized with therapeutic and targeted peptides for the treatment of glioblastoma multiforme. ACS Appl Mater Interfaces. 2018;10:12341–50. [DOI] [PubMed]

96.

Terstappen GC, Meyer AH, Bell RD, Zhang W. Strategies for delivering therapeutics across the blood-brain barrier. Nat Rev Drug Discov. 2021;20:362–83. [DOI] [PubMed]

97.

Qu M, Lin Q, Huang L, Fu Y, Wang L, He S, et al. Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson’s disease. J Control Release. 2018;287:156–66. [DOI] [PubMed]

98.

Cooper JM, Wiklander PBO, Nordin JZ, Al-Shawi R, Wood MJ, Vithlani M, et al. Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov Disord. 2014;29:1476–85. [DOI] [PubMed] [PMC]

99.

Adachi T, Nakamura Y. Aptamers: a review of their chemical properties and modifications for therapeutic application. Molecules. 2019;24:4229. [DOI] [PubMed] [PMC]

100.

Ren X, Zhao Y, Xue F, Zheng Y, Huang H, Wang W, et al. Exosomal DNA aptamer targeting α-synuclein aggregates reduced neuropathological deficits in a mouse Parkinson’s disease model. Mol Ther Nucleic Acids. 2019;17:726–40. [DOI] [PubMed] [PMC]

101.

Kojima R, Bojar D, Rizzi G, Hamri GC, El-Baba MD, Saxena P, et al. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nat Commun. 2018;9:1305. [DOI] [PubMed] [PMC]

102.

Izco M, Blesa J, Schleef M, Schmeer M, Porcari R, Al-Shawi R, et al. Systemic exosomal delivery of shRNA minicircles prevents parkinsonian pathology. Mol Ther. 2019;27:2111–22. [DOI] [PubMed] [PMC]

103.

Picca A, Guerra F, Calvani R, Bucci C, Lo Monaco MR, Bentivoglio AR, et al. Mitochondrial-derived vesicles as candidate biomarkers in Parkinson’s disease: rationale, design and methods of the EXosomes in PArkiNson Disease (EXPAND) Study. Int J Mol Sci. 2019;20:2373. [DOI] [PubMed] [PMC]

104.

Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535:551–5. Erratum in: Nature. 2016;539:123. [DOI] [PubMed] [PMC]

105.

Torralba D, Baixauli F, Sánchez-Madrid F. Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol. 2016;4:107. [DOI] [PubMed] [PMC]

106.

Chang JC, Chao YC, Chang HS, Wu YL, Chang HJ, Lin YS, et al. Intranasal delivery of mitochondria for treatment of Parkinson’s disease model rats lesioned with 6-hydroxydopamine. Sci Rep. 2021;11:10597. [DOI] [PubMed] [PMC]

107.

Dave KM, Dobbins DX, Farinelli MN, Sullivan A, Milosevic J, Stolz DB, et al. Engineering extracellular vesicles to modulate their innate mitochondrial load. Cell Mol Bioeng. 2022;15:367–89. [DOI]

108.

Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. [DOI] [PubMed] [PMC]

109.

Zhao M, Liu S, Wang C, Wang Y, Wan M, Liu F, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate mitochondrial damage and inflammation by stabilizing mitochondrial DNA. ACS Nano. 2021;15:1519–38. Erratum in: ACS Nano. 2021;15:20692. [DOI] [PubMed]

110.

Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18:759–65. [DOI] [PubMed] [PMC]

111.

Trinh D, Israwi AR, Arathoon LR, Gleave JA, Nash JE. The multi-faceted role of mitochondria in the pathology of Parkinson’s disease. J Neurochem. 2021;156:715–52. [DOI] [PubMed]

112.

Gimona M, Brizzi MF, Choo ABH, Dominici M, Davidson SM, Grillari J, et al. Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy. 2021;23:373–80. [DOI] [PubMed]

113.

Moghadasi S, Elveny M, Rahman HS, Suksatan W, Jalil AT, Abdelbasset WK, et al. A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine. J Transl Med. 2021;19:302. [DOI] [PubMed] [PMC]

114.

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

115.

Patel DB, Gray KM, Santharam Y, Lamichhane TN, Stroka KM, Jay SM. Impact of cell culture parameters on production and vascularization bioactivity of mesenchymal stem cell-derived extracellular vesicles. Bioeng Transl Med. 2017;2:170–9. [DOI] [PubMed] [PMC]