Ag-CuO Nanozymes Superior to Commercial Silver-Based Dressings: Synergistic Antibacterial Therapy via PTS-Mediated Starvation and Cuproptosis-Like Death

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Burn wounds are prone to infection, and traditional antibiotics cannot be used locally due to bacterial resistance. As a clinical first-line use of silver ion dressings, their use is often limited due to potential toxic side effects and high costs. To overcome these limitations, a bimetallic nanozyme with multiple antibacterial properties was proposed. CuO nanoflowers were first synthesized via a simple liquid-phase method, and then, Ag ions were doped to synthesize Ag-CuO nanozymes. In vitro/in vivo experiments/RNA sequencing revealed that it not only has a variety of enzyme activities, which can accumulate reactive oxygen species (ROS) for sterilization, but can also cooperate with the starvation-cuproptosis-like death cascade for sterilization. The genes regulating the phosphotransferase system were down-regulated by Ag-CuO nanozymes, which reduced the uptake of carbohydrates needed for energy synthesis by bacteria. The tricarboxylic acid cycle signaling pathway was inhibited, and adenosine triphosphate synthesis was reduced, thus inhibiting its own protection against external stimuli. Moreover, the down-regulation of the lpdA gene, coupled with bacterial starvation, synergistically led to an increase in Cu 2+ influx and an increase in Cu + accumulation, thereby amplifying bacterial cuproptosis-like death and biofilm inhibition. The unique ROS-starvation-cuproptosis-like death sterilization method overcomes the limitation that traditional antibiotics are easily tolerated by bacteria. Importantly, its efficacy was verified in a mouse New Zealand rabbit model, which strongly demonstrated its potential for clinical use in the treatment of drug-resistant bacterial infections, as it has excellent antibacterial activity and the ability to promote angiogenesis compared with those of commercial silver-based dressings with the same silver ion content.

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