Nanozymes are emerging antibacterial agents that catalyze reactive oxygen species to eliminate pathogenic threats; however, their ability to combat multi-drug-resistant infections is still limited by catalytic efficiency, substrate affinity, and stability. This paper reports a novel strategy of incorporating nickel into ultrathin PtPdRh nanosheets to engineer lattice strain, thereby enhancing substrate affinity and boosting enzyme-mimicking catalytic activity.The catalytic efficiency of PtPdRhNi nanozyme (K_cat/K_m = 2.05 × 10^6 m⁻¹ s⁻¹) is 56.5 times higher than that of PtPdRh, maintaining over 90% activity after 15 months. Theoretical calculations indicate that Ni incorporation shifts the d-band center from −1.80 eV to −1.27 eV and strengthens the Pt−O bond, thereby accelerating H₂O₂ → OH.We further demonstrated that the combined treatment of PtPdRhNi and H2O2 can achieve a 100% eradication rate of methicillin-resistant Staphylococcus aureus and Escherichia coli, and can kill over 99.97% of mutant Streptococcus and Porphyromonas gingivalis. In rat models of periodontitis, MRSA-infected skin wounds, and deep abscesses, this catalytic platform can rapidly clear bacteria.Resolve inflammation and regenerate collagen-rich tissues. Transcriptome analysis of MRSA exposed to PtPdRhNi in the presence of H2O2 identified 1,048 differentially expressed genes, revealing respiratory chain and tricarboxylic acid cycle shutdown, weakened antioxidant defenses, energy depletion, oxidative damage, and transcriptome reprogramming.

The spread of antibiotic resistance is becoming a major global public health threat, making it imperative to develop new antibacterial strategies that can bypass traditional resistance mechanisms. Nanozymes, especially those based on noble metals, have shown potential in antibacterial therapy due to their enzyme-like catalytic activity, good stability, and biocompatibility.However, existing noble metal nanoenzymes are often limited by their inherent electronic inertness, resulting in insufficient affinity and catalytic efficiency for substrates such as hydrogen peroxide, making it difficult to effectively fight multidrug-resistant bacteria. How to accurately regulate its electronic structure at the atomic scale has become a key challenge to improve its antibacterial performance.

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DOI: 10.1002/adma.202518526