A ROS-responsive nanoprodrug-engineered phage biotherapy for precision treatment of multidrug-resistant Gram-negative bacterial pneumonia

Multidrug-resistant Gram-negative bacteria (MDR-GNB) pose a significant threat to global healthcare, causing severe morbidity and mortality rates in pneumonia cases. Despite the effectiveness of polymyxins, their clinical use is limited by toxicity and emerging bacterial resistance. Here, we describe a precisely targeting, biohybrid therapeutic platform that combines a polymyxin B-based prodrug nanosystem with an engineered phage. This biohybrid system enables the accumulation of polymyxin B at pathogens and its release in a reactive oxygen species (ROS)-triggered manner at inflamed sites. In vitro and in vivo studies demonstrate that this system shows robust lung distribution and tissue retention, effectively eliminating pathogens, reducing oxidative damage, and alleviating inflammation in a model of bacterial pneumonia. Our findings highlight the potential of this phage-prodrug biohybrid nanoplatform for targeted antibiotic delivery, offering a therapeutic paradigm against infectious diseases caused by MDR-GNB.