Copper phosphate nanozymes combat implant-related infections by inducing cuproptosis-like death and inhibiting the two-component system

Implant-related infections, characterized by recalcitrant biofilm formation, antibiotic resistance, and immune evasion, pose a severe clinical burden in orthopedics due to the limited therapeutic efficacy of conventional approaches. Addressing this challenge requires innovative strategies capable of simultaneously disrupting biofilms and overcoming bacterial defense mechanisms. To address this, we developed flower-like copper phosphate (CuP) nanozymes with dual enzymatic activities (peroxidase- and glutathione peroxidase-like) that synergistically eradicate biofilms for implant-related infections through cuproptosis-like death and two-component system (TCS) inhibition. <i>In vitro</i> antimicrobial experiments demonstrated that CuP nanozymes significantly inhibited and disrupted bacterial biofilms. These CuP nanozymes generate reactive oxygen species (ROS) while depleting glutathione (GSH), disrupting bacterial membranes, and disrupting metabolic processes such as the TCA cycle and glycolysis. Transcriptomic analysis revealed suppressed expression of oxidative phosphorylation genes and quorum-sensing regulators, confirming dual targeting of bacterial viability and communication. <i>In vivo</i>, CuP nanozymes effectively eliminated biofilm infections on implants, reduced inflammatory responses, and demonstrated excellent biocompatibility. By integrating enzymatic ROS amplification, metabolic interference, and TCS inhibition, this strategy offers a transformative approach to combat resistant implant infections, surpassing conventional therapies in both efficacy and safety.