Multimodal electroconductive PLGA-based scaffold orchestrates neuroprotection and regeneration following severe spinal cord injury.

Spinal cord injury (SCI) is a devastating neurological condition that has limited therapeutic options; thus, developing innovative regenerative strategies to treat SCI is necessary. This study presents a multifunctional scaffold system that synergistically combines poly(lactic-co-glycolic acid) and multiple bioactive components such as magnesium hydroxide nanoparticles, decellularized brain extracellular matrix, two-dimensional MXene nanosheets, berberine, sertoli cell-derived extracellular vesicles, and neural progenitor cells. This synergistic design provides a bioactive microenvironment that mitigates inflammation and promotes antioxidative responses while delivering sustained bioactive signals for neural repair. In particular, the conductive property of the scaffold resulting from MXene incorporation facilitates intercellular electrical signaling to provide axonal regeneration. In vitro, the scaffold modulates macrophage polarization toward an anti-inflammatory M2 phenotype, promotes neural differentiation, and reduces oxidative stress. In a complete transection rat model, the scaffold enhances motor function recovery and reduces neuropathic pain. Histological analyses show reduced glial scar formation, enhanced remyelination, and robust axonal regeneration. Molecular studies further confirm the upregulation of anti-inflammatory cytokines and neurotrophic factors, thereby demonstrating the ability of the scaffold to reprogram the injury microenvironment for regeneration. These findings indicate the application potential of this multifunctional scaffold as a transformative therapy for SCI.