Metal-regulated MXene nanozyme with second near-infrared-triggered photothermal and chemodynamic synergy for anti-infection therapy and transcriptomic deciphering of antibacterial mechanisms.

The continuous use of antibiotics and the emergence of multidrug-resistant bacteria, particularly Methicillin-resistant Staphylococcus aureus (MRSA), have become significant global health concerns. Therefore, it is imperative to explore non-antibiotic therapeutic options. Existing antimicrobial modalities, such as single-modality photothermal therapy (PTT), exhibit limited penetration depth and bacterial suppression and do not offer any advantageous biocatalytic activity. To address these challenges, we present a metal-regulated MXene nanozyme, Ag@V2C, designed to facilitate synergistic PTT and chemodynamic therapy (CDT) under second near-infrared (NIR-II) irradiation. The localized surface plasmon resonance of the nanoplatform, along with the silver-decorated V2C MXene, achieves a photothermal conversion efficiency (PCE) of 52 ± 2% for deep-tissue photothermal ablation. Furthermore, Ag@V2C functions as a nanozyme with inherent oxidase and peroxidase activities, generating reactive oxygen species (ROS) for CDT. Under NIR-II irradiation, the catalytic and photothermal effects are significantly enhanced. Insights from density functional theory calculations elucidate the interactions between Ag@V2C and its substrate, as well as the improved catalytic performance. Transcriptomic analysis indicates that treatment with Ag@V2C disrupts key bacterial biosynthetic and metabolic pathways, including aminoacyl-tRNA biosynthesis, pyrimidine metabolism, and central carbon metabolism. Consequently, it interferes with bacterial viability and resistance. In murine models of subcutaneous abscess and acute pneumonia, we demonstrate that Ag@V2C under NIR-II radiation effectively cures deep MRSA infections, promotes wound closure, and alleviates pulmonary inflammation, all while exhibiting good biosafety. This research proposes an effective strategy to combat MRSA infections through metal-regulated nanozyme design, NIR-II-amplified synergistic therapy, and transcriptomic mechanistic insights, showcasing strong translational potential.