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Implant-associated infections mediated by bacterial biofilm colonization remain a major cause of orthopedic prosthesis failure. Although traditional high-dose antibiotic regimens have limited clinical efficacy and often require prosthesis replacement after debridement, such interventions impose a significant psychological and financial burden on patients. To address this challenge, by integrating copper oxide nanoparticles (Cu₂O NPs) with the copper ion complex elesclomol (ES),Engineered ES@Cu2O nanozymes with dual-enzyme activity are designed to combat implant-associated infections by enhancing copper-dependent toxin-like cell death. The ES@Cu2O nanozymes leverage peroxidase-like (POD-like) activity to catalyze the conversion of endogenous hydrogen peroxide (H2O2) into reactive oxygen species (ROS), generating a strong oxidative burst in the biofilm microenvironment. Meanwhile, the glutathione peroxidase-like (GSH-Px-like) activity of ES@Cu2O effectively consumes overexpressed glutathione (GSH), thereby enhancing ROS-mediated therapeutic effects.It is noteworthy that ES exacerbates abnormal intracellular Cu²⁺ accumulation, intensifying mortality similar to that caused by acrylonitrile storage disease. Compared with the Cu-2O treatment group, the ES@Cu₂O treatment group exhibited significantly stronger antibacterial and biofilm eradication capabilities in vitro. RNA sequencing (RNA-seq) showed that in the ES@Cu₂O treatment group, key energy metabolism pathwaysIncluding the TCA cycle, pyruvate metabolism, and oxidative phosphorylation, which were significantly inhibited compared to the Cu-2O treatment group, supporting the mechanism by which ES-mediated Cu²⁺ overload strongly enhances copper-phosphorylation-like cell death. In vivo, ES@Cu₂O demonstrated excellent antibacterial and repair effects in mouse implantation-related infection models, while biosafety assessments confirmed its systemic toxicity to be negligible.Overall, this study demonstrates that the ES@Cu₂O nanozyme with dual enzyme activities can robustly eliminate biofilms and eradicate colonizing bacteria in implant-related infections by enhancing honeycomb-like cell death, proposing a new therapeutic strategy with significant clinical translational potential.
Reference News:
DOI: 10.1002/adfm.202524044
