Harnessing NIR-II-responsive Rh single-atom nanozymes for photothermal-catalytic immunomodulation and eradication of drug-resistant biofilms in deep tissues

The rising incidence of multidrug-resistant (MDR) bacterial infections in deep tissues, such as subcutaneous abscesses and bacterial pneumonia, has become an urgent public health concern. Both conventional antibiotic treatments and nanomaterial-based therapies are inadequate due to their limited catalytic efficiency, poor tissue penetration, and the enhanced resistance they provoke. We report the rational design and synthesis of nitrogen-doped rhodium single-atom catalysts (Rh SACs) that integrate second near-infrared (NIR-II) photothermal conversion with multienzyme mimetic activities. This nanozyme platform employs a synergistic 'photothermal-catalytic' therapy to effectively eliminate MDR pathogens and disrupt biofilms. Density functional theory (DFT) calculations indicate that atomically dispersed Rh sites lower the reaction barrier and optimize the adsorption of intermediates. The presence of rhodium enhances peroxidase and oxidase-mimetic activities under NIR-II irradiation. Transcriptional analysis reveals that Rh SACs modulate inflammation signaling and the immune microenvironment at the molecular level. In mice with methicillin-resistant <i>Staphylococcus aureus</i>-infected abscesses and lung infections, treatment with Rh SACs resulted in nearly complete bacterial clearance, biofilm disruption, and accelerated tissue repair. Additionally, macrophage polarization shifted significantly from M1 to M2. A systematic biosafety assessment demonstrated excellent hemocompatibility and minimal systemic toxicity. This work not only presents an efficient and resistance-free strategy for treating deep tissue infections but also provides crucial structural insights for structure-activity relationship studies in single-atom nanozymes. We strongly believe that nanosystems hold substantial potential for clinical translation in catalytic nanomedicine.