Polyvalent copper oxide nanozymes: Co-delivery of ROS and NO for inducing cuproptosis-like bacterial death against MRSA infections

Abstract

The development of highly effective and low-toxicity antimicrobials is one of the important challenges for combat methicillin-resistant Staphylococcus aureus (MRSA) infections. Recent studies have found that cuproptosis-like bacterial death is an effective strategy to overcome drug resistance. Here, we designed and synthesized a valence in situ conversion of polyvalent copper oxide nanozymes (L-CuxO NPs), which modified L-arginine (L-Arg) to enhance antibacterial ability. In vitro studies showed that L-CuxO NPs can catalyze hydrogen peroxide (H2O2) to produce hydroxyl radical (•OH), mediate NO release, and continuously consume glutathione (GSH) through change of valence state of Cu2+ and Cu+. Importantly, copper overload in bacteria restricts the tricarboxylic acid (TCA) cycle, promoting bacterial cuproptosis-like death. In vivo results confirmed that L-CuxO NPs is not only effective in alleviating acute MRSA lung infection, but also accelerates the healing of MRSA infected wounds. Accordingly, this study provides a new idea for overcoming bacterial resistance and structural innovation of novel nanozymes.