Precise Strain Tuning of PtPdRhNi Nanozyme Boosts Multi‐Pathogen and Multi‐Model Antibacterial Therapy

ABSTRACT Nanozymes are emerging antimicrobial agents that catalyze reactive oxygen species to eliminate pathogenic threats; however, their ability to combat multidrug‐resistant infections remains limited by catalytic efficiency, substrate affinity and instability. Herein, we report a new strategy incorporating Ni into ultrathin PtPdRh nanosheets to engineer lattice strain for enhancing substrate affinity and boosting enzyme‐mimicking catalytic activity. The PtPdRhNi nanozyme achieves a catalytic efficiency (K cat /K m = 2.05 × 10 6 m −1 s −1 ), 56.5‐fold higher than PtPdRh and maintains over 90% activity after 15 months. Theoretical calculations reveal Ni incorporation upshifts the d ‐band center from −1.80 to −1.27 eV and strengthens Pt─O bonding, thus accelerating the activation of H 2 O 2 into ·OH. We further demonstrate that PtPdRhNi co‐treated with H 2 O 2 achieves 100% eradication of methicillin‐resistant Staphylococcus aureus and Escherichia coli , as well as over 99.97% killing of Streptococcus mutans and Porphyromonas gingivalis . Across rat periodontitis, MRSA ‐infected skin wounds and deep abscess models, this catalytic platform enables rapid bacterial clearance, resolves inflammation and regenerates collagen‐rich tissue. Transcriptomic analysis of MRSA exposed to PtPdRhNi with H 2 O 2 identifies 1048 differentially expressed genes, revealing respiratory chain and tricarboxylic acid cycle shutdown, weakened antioxidant defenses, leading to energy exhaustion, oxidative damage and transcriptomic reprogramming.