Mesenchymal stem cell-derived small extracellular vesicles in spinal cord injury: From molecular repair mechanisms to...

Spinal cord injury (SCI) causes permanent neurological disability through a complex sequence of primary mechanical damage and secondary injury cascades, including neuroinflammation, blood-spinal cord barrier disruption, oxidative stress, apoptotic and ferroptotic cell death, demyelination, glial scar formation, and limited axonal regeneration. Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs), particularly small EV preparations frequently reported in the SCI literature as exosomes, have emerged as cell-free therapeutic candidates because they can transfer regulatory proteins, lipids, mRNAs, microRNAs, and other non-coding RNAs to injured neural, glial, immune, and vascular cells. Preclinical studies consistently report improved locomotor recovery and tissue preservation after MSC-EV treatment, with the strongest mechanistic support currently centered on immunomodulation, macrophage/microglial phenotype regulation, NF-κB/MAPK suppression, PI3K/AKT-related survival signaling, NRF2-associated antioxidant responses, and microRNA-dependent remodeling of inflammatory and regenerative networks. Additional evidence supports effects on blood-spinal cord barrier repair, angiogenesis, astrocyte reprogramming, axonal growth, remyelination, and synaptic plasticity, although many of these outcomes remain marker-driven and require stronger causal validation through cargo loss-of-function, pathway blockade, biodistribution, electrophysiology, and circuit-level assays. Bioengineering approaches, including parental-cell preconditioning, cargo enrichment, surface targeting, and hydrogel- or scaffold-assisted sustained delivery, have expanded the therapeutic potential of MSC-EVs but also increase product complexity. Human evidence remains preliminary: early intrathecal administration of allogeneic human umbilical cord MSC-derived EV preparation, reported by the investigators as exosomes, supports feasibility and short-term safety, but efficacy has not been established in adequately powered randomized trials. Using a structured narrative search strategy, explicit eligibility criteria, and a predefined evidence-mapping rule, this review synthesizes mechanistic, preclinical, delivery, and early clinical evidence and argues that translation will depend on standardized product identity, potency-linked release criteria, scalable manufacturing, dose and regimen selection informed by reported protein/particle exposure, administration route, timing, repeat dosing, and clinically meaningful trial design.