Synergistic Antioxidant and Anti-Ferroptosis Therapy via BPNS-Encapsulated Thermoresponsive Chitosan Hydrogel for Spinal Cord Injury Regeneration.

Background: Spinal cord injury (SCI) is a devastating neurological condition with limited therapeutic options. Current clinical interventions predominantly rely on prolonged or high-dose pharmacological regimens, often causing systemic toxicity and adverse events. Although black phosphorus nanosheets (BPNSs) exhibit remarkable reactive oxygen species (ROS)-scavenging capacity to mitigate oxidative damage, their rapid degradation severely compromises their therapeutic efficacy. Methods: This study presents a thermosensitive hydrogel with rapid gelation properties by incorporating different proportions and concentrations of sodium alginate (SA) into a chitosan/β-glycerophosphate (CS/β-GP) hydrogel and loading it with BPNS for the treatment of SCI in rats. In vitro, the physical properties of the composite were characterized and the cytotoxicity and ROS scavenging abilities were assessed using PC12 cells; in vivo, behavioral tests, histopathological analysis, transcriptomics, immunohistochemistry, and Western blotting were performed to explore the therapeutic effects and mechanisms. Results: The results demonstrate that this hydrogel effectively slows BPNS degradation, exhibits a high ROS scavenging capacity, reduces lipid peroxidation, and thereby inhibits ferroptosis and apoptosis, offering neuroprotective effects and promoting motor function recovery. Conclusions: Our findings establish the CS/β-GP/SA-BPNS hydrogel as a multifunctional therapeutic platform for SCI, synergizing sustained drug release with ROS-ferroptosis-apoptosis axis modulation to achieve neuroprotection and functional restoration. This strategy provides a translatable paradigm for combining nanotechnology and biomaterial engineering in neural repair.