A Mucous Permeable Local Delivery Strategy Based on Manganese-Enhanced Bacterial Cuproptosis-like Death for Bacterial Pneumonia Treatment

Bacterial pneumonia is one of the most challenging global infectious diseases with high morbidity and mortality. Considering the antibiotic abuse and resistance of bacterial biofilms, a variety of metal-based materials have been developed. However, due to the high oxygen environment of the lungs, some aerobic infection bacteria have high tolerance to oxygen and ROS, and most of the metal-based materials based on ROS may not achieve good therapeutic effects. Inspired by the sensitivity of cuproptosis to aerobic respiratory cells, we designed a copper composite antibacterial nanoparticle and found that it can effectively induce cuproptosis-like death in the aerobic bacteria of the lungs. To address the challenge of <i>in vivo</i> application of cuproptosis, manganese dioxide was first incorporated to deplete protective glutathione, which can interact with copper and thus hinder the interaction of copper with proteins and assist in antibacterial action through immune enhancement. Cuproptosis-like death also requires a large number of copper ions. To meet this demand, we deliver positively hydrophilic modified composite nanoparticles that effectively penetrate the lung mucus layer directly to the lungs through local administration, and the copper ions are further released rapidly by the acidic environment at the infected site, which can further destroy bacterial biofilms in synergy with manganese. This drug-delivery system can effectively treat pneumonia caused by aerobic bacteria and avoid systemic toxicity that can be caused by large doses of copper.