PEGylated Chitosan-Functionalized Bimetallic Composite Nanoparticles Mediating Bacterial Cuproptosis-Like Death for the Treatment of Pathogen-Induced Pneumonia

Bacterial pneumonia is a significant global infectious disease due to its high contagion and mortality rates. In this study, the mucus-penetrable bimetallic composite nanoparticles (Cu–Mn NPs) with excellent lung-retention abilities and mucus-penetrating capabilities was developed by incorporating manganese dioxide into a copper–gallic acid complex and modifying it with PEGylated chitosan. Specifically, Cu–Mn NPs synergistically induce bacterial cuproptosis-like death, inhibit bacterial growth, eliminate drug-resistant biofilms, and promote macrophage polarization toward the M1 phenotype. In addition, the constructed Cu–Mn NPs could generate abundant reactive oxygen species, which disrupted bacterial membrane integrity, interfered with the respiratory chain, and significantly reduced bacterial virulence. More importantly, in a methicillin-resistant Staphylococcus aureus (MRSA)-infected pneumonia mouse model, treatment with Cu–Mn NPs significantly improved survival rates and reduced inflammatory injury without causing systemic toxicity. These findings show the considerable clinical potential of multifunctional Cu–Mn NPs for the targeted treatment of acute lung diseases associated with MRSA infection.