Hypoxic Neural Stem Cells Enhance Spinal Cord Repair Through HIF‐1a/RAB17‐Driven Extracellular Vesicle Release

ABSTRACT Spinal cord injury (SCI) is a severe and complex condition that can lead to significant physical impairments and affect the life quality of patients. Neural stem cells (NSCs) transplantation holds as a promising therapeutic approach for SCI. However, the challenging post‐SCI microenvironment limits NSCs effectiveness. Our current research has found that transplanted NSCs, though with lower survival and differentiation, still aided in injury repair. Hypoxia was identified as a stressor inducing the release of extracellular vesicles (EVs) from NSCs through HIF‐1α/RAB17 enhancing SCI repair. By extracting and modifying these EVs derived from hypoxia treated NSCs with CAQK/Angiopep2 peptides, we were able to accurately deliver them to the injury site, enhancing recovery without relying on cell survival or differentiation. This study delved into the reparative role and underlying mechanisms of transplanted NSCs in SCI, focusing on their non‐cellular contributions and developed an innovative, targeted strategy for the transplantation of EVs derived from NSCs, offering a cell‐free, precision therapeutic intervention for the treatment of SCI.