This study investigates the application of decellularized tissue matrices (DSCM) hydrogels functionalized with extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) for spinal cord injury (SCI) treatment. The primary focus is on how these composites influence macrophage reprogramming and neural stem cell (NSC) differentiation by modulating Slamf9 expression. MSC-derived EVs were successfully isolated, and DSCM hydrogels were prepared from porcine spinal cords. The composite material, EVs derived from MSCs (DSCM@EVs), was constructed and applied to a mouse SCI model, showing significant enhancement in NSC differentiation and axonal growth, thereby alleviating SCI. Bioinformatics and in vitro cell experiments revealed that DSCM@EVs promote the reprogramming of M1 macrophages to the M2 phenotype, reducing inflammatory responses and facilitating NSC differentiation. RNA-seq analysis identified Slamf9 as a key regulatory gene, with its suppression linked to the observed therapeutic effects. This novel approach demonstrates the potential of DSCM@EVs in SCI repair by modulating the inflammatory environment and promoting neural regeneration, offering a promising strategy for treating SCI and potentially other inflammatory neurological disorders.© 2025. The Author(s).