A Mucous Permeable\nLocal Delivery Strategy Based on\nManganese-Enhanced Bacterial Cuproptosis-like Death for Bacterial\nPneumonia Treatment

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