Repurposing tumor-derived extracellular vesicles with an adhesive carboxymethyl chitosan-based hydrogel for spinal cord injury repair.

Spinal cord injury (SCI) triggers a cascade of pathological events, including persistent neuroinflammation and glial scar formation, which severely hinder axonal regeneration and motor functional recovery. Inspired by the immunosuppressive and regenerative features of the tumor microenvironment, this study introduces a high-reward strategy that repurposes tumor-derived extracellular vesicles (TDEVs) for SCI repair. To ensure localized delivery and enhance safety, TDEVs are incorporated into an injectable adhesive hydrogel composed of carboxymethyl chitosan (CMC) and polydopamine (PDA), crosslinked through Schiff-base chemistry. The resulting TDEVs@CMC-PDA hydrogel adheres firmly to the injured spinal cord and enables sustained release of TDEVs, allowing targeted modulation of the injury microenvironment. In a mouse SCI model, TDEVs@CMC-PDA effectively attenuates neuroinflammation, suppresses glial scar formation, and promotes axonal regrowth and remyelination, ultimately improving motor function. Importantly, biosafety assessments reveal no evidence of systemic toxicity or transcriptional activation of oncogenic pathways. These findings highlight the therapeutic promise and safety of repurposing TDEVs with the adhesive CMC-PDA hydrogel, positioning this strategy as a compelling platform for neural regeneration and beyond.