Three‐Dimensional Biomimetic Aerogel Conduits with Electro‐Ionic‐Immune Coupling Reverse the Pathological Cascade of Spinal Cord Injury

ABSTRACT Spinal cord injury (SCI) triggers a pathological cascade characterized by disrupted electrical signaling, excitotoxicity, neuroinflammation, and oxidative stress, which hinder neural regeneration. To address this complexity, an “electro‐ionic‐immune” synergistic strategy was implemented in a biomimetic aerogel conduit, termed “Gelatin/PLLAf/PPy‐TA@Mg 2+ ” (GPPTM). The aerogel was constructed from a nanofiber matrix composed of gelatin/poly( l ‐lactic acid) doped with polypyrrole nanoparticles and further functionalized with tannic acid and Mg 2+ . It was engineered to form a biomimetic architecture featuring interconnected microporous networks and directional channels. It mimicked the mechanical properties and conductivity of the natural spinal cord, while exerting neuroprotective effects by inhibiting calcium influx, modulating inflammatory responses, scavenging reactive oxygen species, and alleviating mitochondrial dysfunction. Collectively, these features fostered a regenerative microenvironment promoting neural stem cell differentiation and neuronal survival. In SCI model rats, the aerogel markedly suppressed apoptosis and glial scar formation. Ultimately, the synergistic effects of neuronal survival and directed axonal growth facilitated motor and urinary functional recovery. By orchestrating multiple regenerative mechanisms to counteract the pathological progression of the hostile post‐SCI microenvironment, this “electro‐ionic‐immune” design demonstrates clinical translation potential for SCI repair.