Mucous Permeable Nanoparticle for Inducing Cuproptosis‐Like Death In Broad‐Spectrum Bacteria for Nebulized Treatment of Acute Pneumonia

Abstract The emergence of antibiotic‐resistant bacteria has exacerbated the challenge of treating infectious diseases. Quorum sensing (QS), a bacterial communication system regulating virulence and biofilm formation, presents a target for novel therapies. Cuproptosis death is a innovation mode of death, however, this effect may be partially inhibited by glutathione (GSH). Buthionine sulfoximine (BSO) is responsible for GSH biosynthesis and has been identified as a potential promoter of cuproptosis death. Here, Cu 2 O‐BSO NPs with lung adhesion and mucus penetration ability are synthesized by incorporating BSO onto Cu 2 O, and modifying it with DOPA and PEG. Cu 2 O‐BSO NPs demonstrated a broad‐spectrum antibacterial activity against both Gram‐positive and Gram‐negative bacteria, making it a viable treatment option for MRSA‐induced acute pneumonia. Specifically, Cu 2 O‐BSO NPs can synergistically enhance bacterial cuproptosis‐like death, hinder the QS system, eradicate biofilms, reduce the virulence of strains, stimulate the chemotaxis and phagocytosis of macrophages, and ultimately improve in mice with severe pneumonia. This research demonstrated the potential of Cu 2 O‐BSO NPs for a wide‐ranging antibacterial alternative, providing promise for addressing microbial resistance and combatting biofilm formation. Additionally, it established a target and theoretical foundation for the clinical treatment of numerous challenging cases of acute drug‐resistant bacteria.