Trimetallic Pt-Pd-Au alloy nanozymes for multimodal synergistic therapy to overcome deep-seated drug-resistant infections via ROS cascade.

To address the therapeutic challenges posed by deep-tissue drug-resistant bacterial infections, this study innovatively develops a multimodal synergistic therapeutic platform based on platinum-palladium-gold trimetallic alloy nanozymes (PPA). By overcoming the limitations of conventional photodynamic therapy (PDT) and electrodynamic therapy, such as restricted tissue penetration and operational complexity, this research integrates three advantageous strategies: photothermal therapy (PTT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT) to construct a PPA system characterized by hierarchical nanostructures. The nanoplatform achieves efficient penetration through bacterial biofilm barriers attributed to its unique multi-branched architecture while exhibiting ultrasound (US)-laser dual-activated cascade catalytic effects and multimodal synergistic bactericidal mechanisms. Results demonstrate that PPA generates significant temperature gradients (with a photothermal conversion efficiency of 52.21 %) and bursts of reactive oxygen species (ROS) under combined near-infrared laser and US stimulation, effectively disrupting biofilm matrices and eradicating bacteria (with an inhibition ratio of 95 %). Integrated transcriptomic and proteomic analyses reveal that PPA operates through multiple mechanisms including the regulation of oxidative stress pathways, quorum sensing systems, and metabolic networks. Animal models illustrate the capability of PPA to accelerate deep infection wound healing while reducing inflammatory cytokine levels, alongside exhibiting excellent biocompatibility. This study transcends the limitations of traditional single-modal therapies by achieving precise synergy between nanozyme catalytic activity and physical field responses, establishing a novel "diagnosis-treatment-regulation" integrated paradigm for managing deep-seated tissue infections. Through engineered design and surface topological optimization, we successfully resolve the critical balance between nanozyme catalytic efficiency and biosafety, thereby laying the theoretical foundations for developing intelligent anti-infective materials.