Dynamic ROS-responsive injectable hydrogel incorporating nanozymes for spinal cord repair by alleviating oxidative stress and neuronal ferroptosis.

Abstract

Secondary injury following spinal cord injury (SCI) is a key factor leading to neurological dysfunction, yet effective clinical interventions remain lacking. In this study, we developed an injectable, reactive oxygen species (ROS)-responsive composite hydrogel (CeO₂@OPP), comprising cerium oxide (CeO₂) nanozymes embedded in an oxidized alginate/polyvinyl alcohol matrix crosslinked through dynamic boronate ester bonds. The hydrogel exhibits robust adhesiveness, effectively mitigating local hemorrhage and preventing pathological iron accumulation in injured cells. Notably, the hydrogel enables the on-demand release of CeO₂ nanozymes through ROS-triggered hydrogel degradation, achieving sustained scavenging of ROS and alleviation of oxidative stress in the lesion microenvironment. In parallel, the calcium-chelating ability of the hydrogel matrix attenuates excitotoxic stress and restores mitochondrial function. These processes synergetically achieve self-treatment by inhibiting the ferroptosis of neurocytes. In a mouse SCI model, CeO₂@OPP treatment promoted neural regeneration and synaptic remodeling, ultimately leading to a significant improvement in motor function. This facile and biocompatible therapeutic platform provides a purpose-driven strategy to intercept ferroptosis-associated secondary damage after SCI and presents a promising approach for translational intervention in central nervous system repair.