ROS-Responsive Hydrogels Functionalized with Cu/Zn MOF Targeting Oxidative Stress Mitigation and Inflammation Modulation to Promote Spinal Cord Injury Repair

Spinal cord injury (SCI) results in irreversible neurological damage primarily due to secondary processes such as oxidative stress, inflammation, and mitochondrial dysfunction, which hinder functional recovery and currently lack effective targeted treatments. Developing bioactive scaffolds that can dynamically reshape this pathological environment is essential for facilitating neural repair. In this study, we present a ROS-responsive hydrogel scaffold synthesized from quaternized chitosan (QCS) and tannic acid (TA), which is further functionalized with Cu/Zn MOF, designed to create a neuro-permissive microenvironment. By taking advantage of the elevated oxidative levels present at the injury site, this hydrogel functions as an "on-demand" therapeutic system. It demonstrates significant antioxidative properties by effectively scavenging intracellular ROS and preserving mitochondrial function, thereby preventing neuronal apoptosis. Concurrently, the composite regulates the immune microenvironment by inhibiting the polarization of pro-inflammatory M1 macrophages while promoting the reparative M2 phenotype. This dual approach of anti-inflammatory and antioxidative regulation significantly reduces astrogliosis and establishes a favorable permissive environment for tissue reconstruction. In vivo assessments reveal that the Cu/Zn MOF@gel significantly enhances axonal regeneration and remyelination, leading to considerable improvements in both electrophysiological conduction and locomotor function recovery. This study underscores the potential of ROS-responsive hydrogels functionalized with MOFs as a promising therapeutic strategy for addressing oxidative and inflammatory challenges in SCI. Schematic illustration of synthesis, ROS-responsive behavior, and therapeutic mechanism of Cu/Zn MOF@gel for SCI repair. (A) Preparation of an injectable, self-healing QCS/TA hydrogel followed by incorporation of Cu/Zn MOF nanozymes to form the composite hydrogel (Cu/Zn MOF@gel). Under high ROS conditions, the network undergoes ROS-responsive degradation, enabling localized, triggered release of Cu/Zn MOF components. (B) Schematic of targeted local administration of Cu/Zn MOF@gel into the SCI lesion site to fill the defect and provide in situ therapy. (C) The Cu/Zn MOF@gel promote nerve regeneration and facilitate the restoration of motor function by oxidative stress mitigation, mitochondrial protection and inflammation modulation.