Hypoxia-preconditioned NSPCs-derived exosome-loaded scaffold enhances neural regeneration and blood-spinal cord barrier restoration following spinal cord injury

• A responsive hydrogel system was developed to enable sustained and controllable release of exosomes from hypoxia-treated neural stem cells. • The released exosomes continuously modulate inflammation, promote blood vessel growth, and support nerve tissue regeneration. • This delivery system ensures targeted and timely release of bioactive components at the injury site, improving therapeutic precision. • The strategy offers a safe and translationally promising approach for repairing spinal cord injury. Spinal cord injury (SCI) results in the loss of motor and sensory function below the lesion site. Exosomes derived from neural stem/progenitor cells (NSPCs) have shown promise in promoting functional recovery after SCI. However, most studies utilize exosomes secreted under normoxic conditions, which do not accurately reflect the hypoxic microenvironment present post-injury. This study investigates whether exosomes from hypoxia-preconditioned NSPCs (HExos) exert superior therapeutic effects compared to those derived under normoxia (Exos). We fabricated an injectable CEC/PEGDA hydrogel to deliver HExos and Exos and assessed their efficacy in vitro using SCI-mimicking models and in vivo in a murine SCI model. HExos significantly outperformed Exos in mitigating local inflammation, restoring blood-spinal cord barrier (BSCB) integrity, and promoting axonal regeneration. These findings highlight the enhanced therapeutic potential of HExos and present a promising strategy for SCI repair.