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.