Exploration of Neuroprotective Therapy

Table 3. Summary of preclinical evidence for stem cell-derived exosomes in major neurodegenerative disorders.

Disease	Exosome source	Key cargo (miRNAs/proteins)	Mechanistic pathway(s)	Experimental model	Outcome/Effect
Alzheimer’s disease (AD) [1–4]	MSC	miR-21, miR-29c, IDE, neprilysin	↓ Aβ aggregation, ↑ synaptic plasticity, activation of PI3K/Akt, and ERK pathways	Transgenic APP/PS1 mice	Reduced Aβ plaque load, improved memory, restored mitochondrial function
	iPSC	miR-29c	↓ BACE1 activity, ↑ LTP, dendritic spine stability	APP/PS1 and in vitro neuronal models	Improved cognitive scores
	NSC	miR-124, BDNF	↑ Neurogenesis, ↓ astrocytic reactivity	Aβ-induced cell cultures	Reduced neuroinflammation
Parkinson’s disease (PD) [5–7, 43–45]	MSC	miR-133b, catalase, SOD	↑ Neurite outgrowth, ↓ α-syn, antioxidative protection	6-OHDA, MPTP mouse models	Restored dopaminergic signaling, improved motor behavior
Parkinson’s disease (PD) [5–7, 43–45]	NSC	miR-124, miR-146a	Inhibited microglial activation, NF-κB modulation	α-Syn overexpression models	↓ Inflammatory cytokines, ↑ neuronal survival
Ischemic stroke [3, 8, 9, 37, 46]	MSC	miR-21, miR-124, VEGF, BDNF	↑ Angiogenesis, ↑ neurogenesis, activation of PI3K/Akt & MAPK/ERK	MCAO rat/mouse models	↓ Infarct volume, ↑ motor recovery
Ischemic stroke [3, 8, 9, 37, 46]	Hypoxia-primed MSC	miR-146a, miR-199a	↑ Anti-inflammatory potential, ↓ apoptosis	Post-ischemic rodent models	Improved sensorimotor recovery

Return to article view

Akt: protein kinase B; BDNF: brain-derived neurotrophic factor; iPSC: induced pluripotent stem cell; MSC: mesenchymal stem cell; NSC: neural stem cell; PI3K: phosphoinositide 3-kinase; VEGF: vascular endothelial growth factor; α-syn: α-synuclein; 6-OHDA: 6-hydroxydopamine; Aβ: amyloid-β; BACE1: β-site amyloid precursor protein cleaving enzyme 1; ERK: extracellular signal-regulated kinase; IDE: insulin-degrading enzyme; LTP: long-term potentiation; miRNA: microRNA; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; MCAO: middle cerebral artery occlusion; MAPK: mitogen-activated protein kinase.

Declarations

Author contributions

AWI: Conceptualization, Supervision, Writing—original draft, Writing—review & editing. ZKR: Conceptualization, Writing—original draft, Writing—review & editing. HSW: Writing—original draft, Writing—review & editing, Supervision. BS: Writing—original draft, Writing—review & editing. SH: Writing—original draft, Writing—review & editing. SRK: Writing—review & editing. All authors read and approved the submitted version.

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

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

Guo M, Yin Z, Chen F, Lei P. Mesenchymal stem cell-derived exosome: a promising alternative in the therapy of Alzheimer’s disease. Alzheimers Res Ther. 2020;12:109. [DOI] [PubMed] [PMC]

Alhenaky A, Alhazmi S, Alamri SH, Alkhatabi HA, Alharthi A, Alsaleem MA, et al. Exosomal MicroRNAs in Alzheimer’s Disease: Unveiling Their Role and Pioneering Tools for Diagnosis and Treatment. J Clin Med. 2024;13:6960. [DOI] [PubMed] [PMC]

Dementia [Internet]. WHO; c2026 [cited 2025 Jul 17]. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia

GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17:939–53. [DOI] [PubMed] [PMC]

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]

Yiannopoulou KG, Papageorgiou SG. Current and Future Treatments in Alzheimer Disease: An Update. J Cent Nerv Syst Dis. 2020;12:1179573520907397. [DOI] [PubMed] [PMC]

Trounson A, McDonald C. Stem Cell Therapies in Clinical Trials: Progress and Challenges. Cell Stem Cell. 2015;17:11–22. [DOI] [PubMed]

Elsharkasy OM, Nordin JZ, Hagey DW, de Jong OG, Schiffelers RM, Andaloussi SE, et al. Extracellular vesicles as drug delivery systems: Why and how? Adv Drug Deliv Rev. 2020;159:332–43. [DOI] [PubMed]

Fayazi N, Sheykhhasan M, Soleimani Asl S, Najafi R. Stem Cell-Derived Exosomes: a New Strategy of Neurodegenerative Disease Treatment. Mol Neurobiol. 2021;58:3494–514. [DOI] [PubMed] [PMC]

10.

Park SH, Lee EK, Yim J, Lee MH, Lee E, Lee YS, et al. Exosomes: Nomenclature, Isolation, and Biological Roles in Liver Diseases. Biomol Ther (Seoul). 2023;31:253–63. [DOI] [PubMed] [PMC]

11.

Antonyak MA, Cerione RA. Emerging picture of the distinct traits and functions of microvesicles and exosomes. Proc Natl Acad Sci U S A. 2015;112:3589–90. [DOI] [PubMed] [PMC]

12.

Wang W, Zhu N, Yan T, Shi YN, Chen J, Zhang CJ, et al. The crosstalk: exosomes and lipid metabolism. Cell Commun Signal. 2020;18:119. [DOI] [PubMed] [PMC]

13.

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]

14.

Li XX, Yang LX, Wang C, Li H, Shi DS, Wang J. The Roles of Exosomal Proteins: Classification, Function, and Applications. Int J Mol Sci. 2023;24:3061. [DOI] [PubMed] [PMC]

15.

Shahsavandi Y, Banaeian F, Jafarinia M, Nasri F, Shapoori S. miRNAs from mesenchymal-stem-cell-derived extracellular vesicles: Emerging players in regenerative medicine and disease therapy. Mol Ther Nucleic Acids. 2025;36:102715. [DOI] [PubMed] [PMC]

16.

Liang X, Zhang L, Wang S, Han Q, Zhao RC. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci. 2016;129:2182–9. [DOI] [PubMed]

17.

Wang W, Zhao Y, Li H, Zhang Y, Jia X, Wang C, et al. Exosomes secreted from mesenchymal stem cells mediate the regeneration of endothelial cells treated with rapamycin by delivering pro-angiogenic microRNAs. Exp Cell Res. 2021;399:112449. [DOI] [PubMed]

18.

Cao L, Sun K, Zeng R, Yang H. Adipose-derived stem cell exosomal miR-21-5p enhances angiogenesis in endothelial progenitor cells to promote bone repair via the NOTCH1/DLL4/VEGFA signaling pathway. J Transl Med. 2024;22:1009. [DOI] [PubMed] [PMC]

19.

Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res. 2016;64:831–40. [DOI] [PubMed]

20.

Du W, Zhang K, Zhang S, Wang R, Nie Y, Tao H, et al. Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer. Biomaterials. 2017;133:70–81. [DOI] [PubMed]

21.

Merino-González C, Zuñiga FA, Escudero C, Ormazabal V, Reyes C, Nova-Lamperti E, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote Angiogenesis: Potencial Clinical Application. Front Physiol. 2016;7:24. [DOI] [PubMed] [PMC]

22.

Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17. [DOI] [PubMed]

23.

Hu WJ, Wei H, Cai LL, Xu YH, Du R, Zhou Q, et al. Magnetic targeting enhances the neuroprotective function of human mesenchymal stem cell-derived iron oxide exosomes by delivering miR-1228-5p. J Nanobiotechnology. 2024;22:665. [DOI] [PubMed] [PMC]

24.

Iranpanah A, Kooshki L, Moradi SZ, Saso L, Fakhri S, Khan H. The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases. Pharmaceutics. 2023;15:1006. [DOI] [PubMed] [PMC]

25.

Nasirishargh A, Kumar P, Ramasubramanian L, Clark K, Hao D, Lazar SV, et al. Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection. World J Stem Cells. 2021;13:776–94. [DOI] [PubMed] [PMC]

26.

Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008;18:350–9. [DOI] [PubMed]

27.

Reza-Zaldivar EE, Hernández-Sapiéns MA, Gutiérrez-Mercado YK, Sandoval-Ávila S, Gomez-Pinedo U, Márquez-Aguirre AL, et al. Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer’s disease. Neural Regen Res. 2019;14:1626–34. [DOI] [PubMed] [PMC]

28.

Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288:7105–16. [DOI] [PubMed] [PMC]

29.

Ge X, Guo M, Hu T, Li W, Huang S, Yin Z, et al. Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI. Mol Ther. 2020;28:503–22. [DOI] [PubMed] [PMC]

30.

Kandeel M, Morsy MA, Alkhodair KM, Alhojaily S. Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities. Biomolecules. 2023;13:1250. [DOI] [PubMed] [PMC]

31.

Xunian Z, Kalluri R. Biology and therapeutic potential of mesenchymal stem cell-derived exosomes. Cancer Sci. 2020;111:3100–10. [DOI] [PubMed] [PMC]

32.

Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31:2737–46. [DOI] [PubMed] [PMC]

33.

Li D, Zhang P, Yao X, Li H, Shen H, Li X, et al. Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury. Front Neurosci. 2018;12:845. [DOI] [PubMed] [PMC]

34.

Ren ZW, Zhou JG, Xiong ZK, Zhu FZ, Guo XD. Effect of exosomes derived from MiR-133b-modified ADSCs on the recovery of neurological function after SCI. Eur Rev Med Pharmacol Sci. 2019;23:52–60. [DOI] [PubMed]

35.

Foo JB, Looi QH, Chong PP, Hassan NH, Yeo GEC, Ng CY, et al. Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine. Stem Cells Int. 2021;2021:2616807. [DOI] [PubMed] [PMC]

36.

Vogel AD, Upadhya R, Shetty AK. Neural stem cell derived extracellular vesicles: Attributes and prospects for treating neurodegenerative disorders. EBioMedicine. 2018;38:273–82. [DOI] [PubMed] [PMC]

37.

Liu YY, Li Y, Wang L, Zhao Y, Yuan R, Yang MM, et al. Mesenchymal stem cell-derived exosomes regulate microglia phenotypes: a promising treatment for acute central nervous system injury. Neural Regen Res. 2023;18:1657–65. [DOI] [PubMed] [PMC]

38.

Lai X, Wang Y, Wang X, Liu B, Rong L. miR-146a-5p-modified hUCMSC-derived exosomes facilitate spinal cord function recovery by targeting neurotoxic astrocytes. Stem Cell Res Ther. 2022;13:487. [DOI] [PubMed] [PMC]

39.

Yang Q, Huang Q, Hu Z, Tang X. Potential Neuroprotective Treatment of Stroke: Targeting Excitotoxicity, Oxidative Stress, and Inflammation. Front Neurosci. 2019;13:1036. [DOI] [PubMed] [PMC]

40.

Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases. Cells. 2019;8:1605. [DOI] [PubMed] [PMC]

41.

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]

42.

Wan T, Huang Y, Gao X, Wu W, Guo W. Microglia Polarization: A Novel Target of Exosome for Stroke Treatment. Front Cell Dev Biol. 2022;10:842320. [DOI] [PubMed] [PMC]

43.

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]

44.

Sun M, Chen Z. Unveiling the Complex Role of Exosomes in Alzheimer’s Disease. J Inflamm Res. 2024;17:3921–48. [DOI] [PubMed] [PMC]

45.

Mavroudis I, Balmus IM, Ciobica A, Nicoara MN, Luca AC, Palade DO. The Role of Microglial Exosomes and miR-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury. Life (Basel). 2023;13:1924. [DOI] [PubMed] [PMC]

46.

Allogenic mesenchymal stem cell derived exosome in patients with acute ischemic stroke [Internet]. [cited 2025 Jul 17]. Available from: https://clinicaltrials.gov/study/NCT03384433

47.

The Safety and the Efficacy Evaluation of Allogenic Adipose MSC-Exos in Patients With Alzheimer’s Disease [Internet]. [cited 2025 Aug 25]. Available from: https://clinicaltrials.gov/study/NCT04388982

48.

Khan H, Pan JJ, Li Y, Zhang Z, Yang GY. Native and Bioengineered Exosomes for Ischemic Stroke Therapy. Front Cell Dev Biol. 2021;9:619565. [DOI] [PubMed] [PMC]

49.

Rastogi S, Sharma V, Bharti PS, Rani K, Modi GP, Nikolajeff F, et al. The Evolving Landscape of Exosomes in Neurodegenerative Diseases: Exosomes Characteristics and a Promising Role in Early Diagnosis. Int J Mol Sci. 2021;22:440. [DOI] [PubMed] [PMC]

50.

Li Y, Tang Y, Yang GY. Therapeutic application of exosomes in ischaemic stroke. Stroke Vasc Neurol. 2021;6:483–95. [DOI] [PubMed] [PMC]

51.

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]

52.

Lotfy A, AboQuella NM, Wang H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem Cell Res Ther. 2023;14:66. [DOI] [PubMed] [PMC]

53.

Song J, Zhou D, Cui L, Wu C, Jia L, Wang M, et al. Advancing stroke therapy: innovative approaches with stem cell-derived extracellular vesicles. Cell Commun Signal. 2024;22:369. [DOI] [PubMed] [PMC]

54.

Wang CK, Tsai TH, Lee CH. Regulation of exosomes as biologic medicines: Regulatory challenges faced in exosome development and manufacturing processes. Clin Transl Sci. 2024;17:e13904. [DOI] [PubMed] [PMC]

55.

Verma N, Arora S. Navigating the Global Regulatory Landscape for Exosome-Based Therapeutics: Challenges, Strategies, and Future Directions. Pharmaceutics. 2025;17:990. [DOI] [PubMed] [PMC]

56.

Akhavan O, Ghaderi E, Shirazian SA. Near infrared laser stimulation of human neural stem cells into neurons on graphene nanomesh semiconductors. Colloids Surf B Biointerfaces. 2015;126:313–21. [DOI] [PubMed]

57.

Li N, Zhang Q, Gao S, Song Q, Huang R, Wang L, et al. Three-dimensional graphene foam as a biocompatible and conductive scaffold for neural stem cells. Sci Rep. 2013;3:1604. [DOI] [PubMed] [PMC]

58.

Akhavan O. Graphene scaffolds in progressive nanotechnology/stem cell-based tissue engineering of the nervous system. J Mater Chem B. 2016;4:3169–90. [DOI] [PubMed]

59.

Fan L, Liu C, Chen X, Zheng L, Zou Y, Wen H, et al. Exosomes-Loaded Electroconductive Hydrogel Synergistically Promotes Tissue Repair after Spinal Cord Injury via Immunoregulation and Enhancement of Myelinated Axon Growth. Adv Sci (Weinh). 2022;9:e2105586. [DOI] [PubMed] [PMC]

60.

Liu M, Zhang W, Han S, Zhang D, Zhou X, Guo X, et al. Multifunctional Conductive and Electrogenic Hydrogel Repaired Spinal Cord Injury via Immunoregulation and Enhancement of Neuronal Differentiation. Adv Mater. 2024;36:e2313672. [DOI] [PubMed]

61.

Zhang S, Cheng Z, Wang Y, Han T. The Risks of miRNA Therapeutics: In a Drug Target Perspective. Drug Des Devel Ther. 2021;15:721–33. [DOI] [PubMed] [PMC]

62.

Diener C, Keller A, Meese E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 2022;38:613–26. [DOI] [PubMed]

63.

Bereczki Z, Benczik B, Balogh OM, Marton S, Puhl E, Pétervári M, et al. Mitigating off-target effects of small RNAs: conventional approaches, network theory and artificial intelligence. Br J Pharmacol. 2025;182:340–79. [DOI] [PubMed]