Cu₂MoS₄ nanozymes reduced bacterial defenses through a dual mechanism to amplify cuproptosis-like death and accelerate the healing of burn-infected wounds.

Abstract

Burn injuries disrupt the skin barrier function, significantly predisposing patients to bacterial invasion. With the widespread use of antibiotics, bacteria have evolved various resistance mechanisms, significantly weakening the efficacy of traditional antibiotics. The application of copper-based nanozymes is still limited by issues such as concentration dependence and bacterial defense. Here, hollow-structured copper-molybdenum bimetallic Cu₂MoS₄ nanozymes were successfully synthesized using a simple hydrothermal method. <i>In vitro</i> antibacterial experiments showed that Cu₂MoS₄ nanozymes have multiple types of enzyme activities producing a robust burst of ROS that directly kill bacteria. Transcriptomic analysis demonstrated that the expression of the <i>lpdG</i> gene was downregulated by Cu₂MoS₄ nanozymes, resulting in aberrant intracellular copper retention and thereby inducing a cuproptosis-like death. Moreover, the transcription of genes pertinent to the arginine deiminase (ADI) pathway was downregulated by Cu₂MoS₄ nanozymes, resulting in impaired ATP production in deep-layer biofilm bacteria and disruption of their metabolic processes, thereby contributing to a reduction in bacterial defense. Concurrently, the expression of <i>sodB</i> and <i>ahpC</i> was directly inhibited by the molybdenum component, which attenuated the bacterial antioxidant defense system and consequently increased susceptibility to ROS-mediated damage. The downregulation of bacterial defenses induces further intracellular copper ion accumulation, synergistically amplifying the cuproptosis-like death and enhancing bactericidal capability. In animal experiments, tissue inflammation was reduced and angiogenesis as well as granulation tissue regeneration were promoted, which effectively accelerated wound healing. The bimetallic copper/molybdenum nanozyme-based multi-mechanistic synergistic antibacterial strategy proposed herein provides a novel clinical strategy for the targeted therapy of antibiotic-resistant bacterial infections following burns.