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.