Adaptive Phenol-Based Hydrogel Embedded with Metformin Nanoparticles Targets Oxidative Stress and Ferroptosis for Spinal Cord Injury Repair

Spinal cord injury (SCI) causes irreversible neurological damage largely due to secondary processes such as ferroptosis and inflammation response, which hinder functional recovery and lack effective targeted treatments. Ferroptosis, an iron-dependent form of cell death driven by oxidative stress, and a pro-inflammatory microenvironment contribute significantly to neuronal loss after SCI. To address these challenges, we developed MCPAD, an injectable, self-healing nanocomposite hydrogel incorporating metformin-loaded PLGA nanoparticles (Met@PLGA NPs) and phenol-derived dynamic cross-linked network (CPAD). This multifunctional platform enables targeted suppression of ferroptosis and immunomodulation. <i>In vitro</i>, MCPAD significantly enhanced neuronal viability by regulating iron homeostasis and upregulating antioxidant defenses. <i>In vivo</i>, it reduced reactive oxygen species (ROS) accumulation, glial scarring, and inflammatory cytokine expression, while promoting axonal regeneration and synaptic remodeling. Treated animals exhibited greatly improved locomotor recovery and tissue preservation. Biochemical assessments confirmed systemic biosafety. These findings demonstrate the therapeutic potential of MCPAD as a biological responsive platform that reprograms the injury microenvironment to support functional neural repair after SCI.