Degradation-Activatable Nanozyme via Metal-Peptide Co-Design for Sustained Antioxidant Therapy in Traumatic Brain Injury

Conventional antioxidants and nanozymes often suffer from short half-lives and irreversible deactivation during biodegradation, severely limiting their efficacy in prolonged oxidative stress conditions like traumatic brain injury (TBI). Herein, we report a degradation-activatable nanozyme, C─Cu SA/MXene, via rational metal-peptide co-design that uniquely decouples catalytic longevity from structural persistence. By anchoring Cu single atoms onto biodegradable Mo 2 C MXene and functionalizing it with cysteine-rich CAQK peptide, we engineer a system where scaffold degradation enables in situ chelation of released Cu 2+ via Cu-S coordination, forming a stable CAQK-Cu complex retaining >80% of its original superoxide dismutase (SOD)-like activity (29 904.3 U/mg), which compares favorably to the referenced standard activity of natural SOD. This system also exhibits catalase-like activity for dual ROS scavenging. Spectroscopic and DFT analyses confirm Cu-S bonding narrows the HOMO-LUMO gap (0.05 eV) and preserves the redox-active electronic structure. In a murine TBI model, C─Cu SA/MXene-derived elements exhibit enhanced retention and preferential accumulation at injury sites, engaging the injured microenvironment, reduce lesion area 62%, increase hippocampal neuronal survival 1.7-fold, restore spatial memory, and activate PI3K/AKT pro-survival pathway. Critically, the material is metabolically cleared within 7 days without systemic toxicity, demonstrating a new degradation-resilient nanozyme platform for sustained ROS scavenging and TBI neuroprotection.