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REVIEW ARTICLE

Neural stem cell-derived exosomes as a regenerative strategy for traumatic brain injury

Nancy Choon-Si Ng1* ,  Rebecca Shin-Yee Wong1 ,  Kuang Zhe Lee2
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1 Department of Medical Education, Sir Jeffrey Cheah Sunway Medical School, Faculty of Medical and Life Sciences, Sunway University, Petaling Jaya, Selangor, Malaysia
2 School of Psychology, Faculty of Medical and Life Sciences, Sunway University, Petaling Jaya, Selangor, Malaysia
Advanced Neurology, 025430101 https://doi.org/10.36922/AN025430101
Received: 22 October 2025 | Revised: 3 December 2025 | Accepted: 3 December 2025 | Published online: 23 December 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide, and current management rarely restores higher-order neurological function. Neural stem cell (NSC) transplantation offers regenerative potential but is constrained by poor graft survival, immune rejection, tumorigenic risk, and challenges in crossing the blood–brain barrier (BBB). These limitations have driven interest in exosome-based cell-free strategies. Human NSC-derived exosomes (hNSC-Exos) can cross the BBB and deliver neurotrophic factors and microRNAs to injured neural circuits, providing a biologically aligned vector for TBI treatment. This narrative review synthesizes evidence on hNSC-Exos as regenerative agents for TBI. We summarize their neurotrophic and neuroprotective properties and key mechanisms in preclinical models, including signal transducer and activator of transcription 3-mediated microglial polarization, phosphatase and tensin homolog-induced kinase 1/Parkin-dependent mitophagy, phosphoinositide 3-kinase/protein kinase B anti-apoptotic signaling, and extracellular signal-regulated kinase 1/2-driven synaptic plasticity, alongside effects on angiogenesis and BBB restoration. This review examines major translational barriers: donor and culture-related heterogeneity, the lack of standardized, good manufacturing practice-compatible isolation and characterization methods, limited biodistribution and dosing data, and the absence of early clinical trials in TBI. Finally, the review outlines priorities in exosome engineering, intranasal and other minimally invasive delivery routes, and biomarker-based potency assays to advance hNSC-Exos toward clinically actionable, cell-free regenerative therapies for TBI.

Graphical abstract
Keywords
Exosomes
Neural stem cells
Neuroregeneration
Translational medicine
Traumatic brain injury
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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