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

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.