MSC-derived extracellular vesicle-associated miRNAs in CNS diseases: mechanisms of microglial polarization and therapeutic implications

Microglia-mediated neuroinflammation contributes to the pathogenesis of many central nervous system (CNS) diseases. After injury or infection, microglia can adopt pro-inflammatory programs that amplify neuronal damage. By contrast, reparative microglial states support inflammatory resolution, tissue repair and regeneration. Strategies that redirect harmful microglial activation toward reparative programs therefore have therapeutic relevance. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), particularly small EV-enriched preparations, are increasingly studied as low-immunogenicity carriers of regulatory cargo. EV-associated microRNAs (miRNAs) are among the major payloads implicated in immunomodulation. This review synthesizes how MSC-EV-associated miRNAs regulate microglial polarization and neuroinflammation through TLR/NF-κB, MAPK, JAK/STAT, PI3K/Akt and Wnt/β-catenin signaling. We discuss evidence from ischemic stroke, traumatic brain injury, spinal cord injury, Alzheimer’s disease and sepsis-associated encephalopathy, and highlight EV terminology, donor source, species context and translational comparability as key barriers for future development.