Neural stem cell-derived extracellular vesicle non-coding RNAs in cerebral ischemia-reperfusion injury: recipient-cell mechanisms, evidence strength, and translational challenges

Neural stem cell-derived extracellular vesicles (NSC-EVs) are being studied as cell-free interventions after cerebral ischemia-reperfusion injury (CIRI), but the evidence that a specific non-coding RNA (ncRNA) is the active therapeutic component is uneven. This critical narrative review separates vesicle-associated RNA detection, experimental RNA delivery, target engagement, and cargo-specific causal necessity. An explicitly context-sensitive three-tier framework is applied alongside a domain-by-domain evidence matrix that distinguishes direct ischemia evidence from lineage-adjacent, hypoxia-only, transplantation-associated, and cross-disease observations. Among the studies reviewed, engineered human NSC-EVs enriched with miR-125a-5p provide comparatively direct evidence for IKBKG/NF-κB pathway modulation in a rat transient middle cerebral artery occlusion model; however, effectiveness of engineered loading does not establish that endogenous EV miR-125a-5p is required for unmodified-product activity. The miR-150-3p/CASP2 study supports a neuronal survival mechanism in oxygen-glucose deprivation and an MCAO-associated brain-injury model, without establishing direct microglial reprogramming. miR-362-3p/MCAM/Wnt-β-catenin, miR-9/Hes1, and hNPC-EV miR-100-5p/NOX4 extend the experimental picture toward endogenous repair and vascular responses but retain important limitations in cargo necessity, model match, or cell lineage. hNSC transplantation-associated miR-204-5p/EFNB3 cannot be assumed to represent purified NSC-EV action. Spinal cord injury, miR-124, lncRNA, and circRNA observations are explicitly considered indirect for a CIRI-specific NSC-EV claim. This review identifies experimental design and reporting gaps, distinguishes observed dosing from proposed intervention windows, and outlines falsifiable, rather than clinically established, translational priorities. The updated PubMed and Web of Science export audit identified 150 distinct title/abstract records from 224 primary-database records and additionally highlighted an NSC-EV miR-128-3p/oligodendrocyte progenitor cell repair axis, while preserving a clear distinction between title/abstract screening and definitive full-text causal appraisal.