Aug 2026· Cells· Vol 15, pp. 1540· 0 citations· 208 references
TL;DR
This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice.
Abstract
Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action—paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs—while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood–brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies—MSCs as adjuncts to gene or enzyme replacement therapy—and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice.
Abstract Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.
Lu-Ming Pan, Bao-Cai Liu, Jing-Jian Xu et al.· International Journal of Nan...· 0 citations
This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system and discusses how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation.
Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple Sclerosis (MS), represent a substantial and growing global health burden, collectively accounting for millions of disability-adjusted life years (DALYs) worldwide and severely impacting cognition, mood, behavior, and motor function. Current therapies, particularly small-molecule drugs, are challenged by the blood-brain barrier (BBB), resulting in poor central nervous system (CNS) bioavailability, systemic adverse effects, and suboptimal patient adherence, underscoring the urgent need for novel delivery platforms. Exosomes, endogenous nanoscale extracellular vesicles (30-150 nm) derived from sources such as mesenchymal stem cells, neural stem cells, and immune cells, have emerged as highly promising biogenic drug carriers owing to their low immunogenicity, inherent biocompatibility, cargo versatility (proteins, mRNA, miRNA), and unique innate ability to cross the BBB, positioning them as superior alternatives to synthetic nanocarriers such as liposomes, niosomes, and solid lipid nanoparticles for targeted CNS delivery. This review provides a comprehensive overview of exosome biology and therapeutics for AD, PD, and MS, covering classification, isolation and characterization methods, drug-loading strategies and a comparative analysis of administration routes (intravenous, intracerebral, intrathecal, intra-arterial, and intranasal). Particular emphasis is placed on the intranasal route, which offers a non-invasive, direct nose-to-brain pathway via the olfactory and trigeminal nerves, effectively bypassing the BBB while minimizing systemic exposure. The review also examines the dual therapeutic and pathological roles of exosomes in BBB function, and emphasizes preclinical and early clinical evidence across AD, PD, and MS. Finally, the review outlines the major manufacturing, regulatory, and standardization hurdles that must be addressed including GMP-grade scale-up, consistent particle-based dosing benchmarks, and large placebo-controlled trials before intranasal exosome therapeutics can progress from promising preclinical candidates to approved disease-modifying treatments for neurodegenerative disorders.
Rajashree Hirlekar, Srushti Agnihotri, Shalom Sathe et al.· Biochemical and Biophysical...· 0 citations
Neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and post-stroke sequelae, and rare disorders, including amyotrophic lateral sclerosis and multiple system atrophy, are characterized by complex neuroinflammatory processes and pathogenic protein aggregation. Natural killer and γδT cells, as pivotal immune effector cells, possess unique immunoregulatory and pathologic protein clearance capabilities, making these cells promising candidates for adoptive immunotherapy strategies. This review comprehensively discusses the synergistic mechanisms by which natural killer and γδT cells cross the blood-brain barrier and eliminate pathogenic proteins. Moreover, the mechanisms by which these cells modulate neuroinflammation and eliminate autoreactive T cells in the central nervous system are elucidated. The multifaceted roles across various neurodegenerative conditions are explored and the potential for clinical translation is evaluated. This review aims to provide theoretical and practical guidance for the development of innovative immune cell-based therapies targeting neurodegenerative diseases by integrating current research advances and identifying existing challenges.
Zhifeng Wu, Xiao-Lin Chen, Tingting Gan et al.· Neuropharmacology and Therap...· 0 citations
Sandhoff disease (SD) is a fatal lysosomal storage disorder caused by β-N-acetylhexosaminidase deficiency, resulting in GM2 ganglioside accumulation, severe neurodegeneration, and chronic neuroinflammation. While enzyme-restoring therapies, such as AAV gene transfer, effectively target the primary enzymatic deficit, neuroinflammation persists and contributes to disease progression, motivating the development of anti-inflammatory adjuncts alongside disease-modifying interventions. Extracellular vesicles released by mesenchymal stromal cells (MSC-EVs) are acellular lipid nanoparticles that contain immunomodulatory molecules and can cross physical barriers, without immunogenicity issues. These features make MSC-EVs promising candidates for anti-inflammatory therapeutics targeting neuropathology. The anti-inflammatory potency of MSC-EVs is increased by priming parent MSCs with pro-inflammatory cytokines, resulting in IFEVs, as referred to in this study. Here, we evaluated the in vitro anti-inflammatory effects of IFEVs in a feline model of SD. IFEVs reduced SD neuroinflammation, lowering IL-6, TNF-α, and IL-1β protein levels in SD neuronal-mixed glia, with concordant transcriptional downregulation of NF-κB/p65 and NLRP3 components and upregulation of arginase 1 mRNA after 48 h of treatment. In SD peripheral blood mononuclear cells, IFEVs significantly increased the proportion of regulatory T cells and the Treg/T-effector cell ratio without inducing cytotoxicity. Together, these findings demonstrate that IFEVs reduced neuroinflammation and altered blood-circulating T-cell populations in an in vitro SD model, supporting their further preclinical development as a complementary immunomodulatory therapy for SD.
This comprehensive review summarizes current research on SC-exosomes in renal diseases, with emphasis on their biological characteristics, therapeutic mechanisms, preclinical evidence, and translational challenges.
Qikai Luo, Nan Yang, Yiwei Shang et al.· Stem Cell Research & The...· 0 citations
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