Human Umbilical Cord Mesenchymal Stem Cells and Their Extracellular Vesicles in Neurological Disorders: Mechanisms, Delivery Strategies, and a Translational Roadmap.

BACKGROUND: Neurological disorders-including ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neurodegenerative disease, chronic neuropathic and inflammatory pain, peripheral nerve injury, and selected psychiatric and neurodevelopmental disorders-remain major causes of death and disability. Human umbilical cord mesenchymal stromal cells (hUC-MSCs) and their extracellular vesicles (EVs) are being investigated as regenerative and immunomodulatory products, but translation is constrained by product heterogeneity, limited direct clinical evidence, uncertain CNS exposure, and incompletely validated potency assays.

MAIN BODY: This narrative review critically compares hUC-MSC and hUC-MSC-EV evidence by indication, model, route, dose, mechanism, outcome, and clinical stage. It distinguishes direct product-specific findings from contextual evidence involving other MSC products. Mechanistic signals include innate immune reprogramming, attenuation of inflammasome activity and oxidative stress, neurovascular-unit protection, and support of angiogenesis, synaptic remodeling, and axonal repair. We evaluate delivery-route limitations, biomaterial-assisted retention, manufacturing and characterization requirements, and a staged translational roadmap aligned with established MSC and EV standards.

CONCLUSION: The evidence base is promising but predominantly preclinical, heterogeneous, and weighted toward cell-based studies. Direct clinical evidence is currently concentrated in spinal cord injury and is insufficient to establish efficacy. Progress requires product-specific reporting, dose-normalized biodistribution, validated mechanism-linked potency assays, manufacturing comparability, multicenter replication, and randomized trials with prespecified target-engagement and functional endpoints.