Inhalable Microenvironment‐Responsive and Self‐Adaptive AuCu Bimetallic Clusterzyme‐Based Microgel for Spatiotemporally Precise Therapy of Bacterial Pneumonia

ABSTRACT Bacterial pneumonia remains a significant clinical challenge mainly due to increasing drug resistance and the limited controllability of available antimicrobial strategies. Herein, an inhalable, hypoxia‐responsive clusterzyme‐engineered microgel system (NC@mGels) is developed for spatiotemporally controlled therapy of bacterial pneumonia. NC@mGels enable the site‐specific release of functional AuCu bimetallic clusterzymes, triggered by the hypoxia‐sensitive supramolecular interactions between β‐cyclodextrin and azobenzene, thereby enhancing the tissue penetration while minimizing side effects. The encapsulated AuCu clusterzymes possess conspicuous pH‐adaptive enzyme‐like activities, which exhibit peroxidase‐like properties in an acidic infection microenvironment. A remarkable elimination efficiency of 99.4 % and 99.9 % toward Methicillin‐Resistant Staphylococcus aureus and Pseudomonas aeruginosa can be achieved at a concentration down to 1.25 and 2.5 µg mL −1 , respectively. Consequently, NC@mGels demonstrate a potent antibacterial effect against both planktonic bacteria and biofilms under hypoxic conditions. In contrast, AuCu clusterzymes switch to catalase‐like activity in physiological neutral conditions, greatly mitigating the hypoxic microenvironment of dysfunctional cells. In vivo experiments further validate that NC@mGels can significantly eliminate the bacterial infection and alleviate the infection‐induced hypoxia, thereby promoting the structural and functional recovery of lungs. This work provides a promising strategy for precisely engineering multifunctional clusterzyme‐based nanotherapeutics toward intelligently combating multidrug‐resistant infections.