Glia cell-derived extracellular vesicles as modulators in spinal cord injury repair

STUDY DESIGN: Narrative review. OBJECTIVES: The aim of this review was to summarize and critically evaluate current evidence on glial cell-derived extracellular vesicles (EVs) as therapeutic mediators in spinal cord injury (SCI), with a focus on their cell-specific functions and phase-dependent effects. METHODS: We narratively synthesized preclinical in vitro and in vivo studies investigating EVs derived from astrocytes, microglia, oligodendrocytes, Schwann cells, and olfactory ensheathing cells in the context of spinal cord injury and related central nervous system pathologies. RESULTS: Glial cell-derived EVs exhibit diverse and cell-type-specific effects following SCI. Astrocyte-derived EVs (ADEVs) contain neuroprotective proteins and microRNAs that regulate inflammation and support neural repair. Microglia-derived EVs (MGEVs) display dual roles, with pro-inflammatory EVs exacerbating secondary injury, while anti-inflammatory EVs promote recovery. Oligodendrocyte-derived EVs (ODEVs) contribute to metabolic support and remyelination but may also carry inhibitory molecules that limit axonal regeneration. Schwann cell-derived EVs (SCEVs) reduce scar formation and enhance axonal growth, in some models outperforming Schwann cell transplantation. Olfactory ensheathing cell-derived EVs (OECEVs) promote axonal regeneration, likely through modulation of the extracellular environment and enhanced debris clearance. Across injury phases, glial EVs may protect the blood-brain barrier in the acute stage, modulate inflammation and angiogenesis in the subacute stage, and support axonal regrowth, remyelination, and synaptic remodeling in the chronic stage. CONCLUSIONS: Glial cell-derived extracellular vesicles represent a promising, cell-free therapeutic strategy for SCI. While preclinical evidence highlights substantial regenerative and immunomodulatory potential, challenges remain regarding EV isolation, targeting, and delivery. Addressing these limitations will be essential for advancing clinical translation.