Bimetal‐Phenolic Framework to Combat Bacterial Infections via Synergistic Biofilm Dispersal, Bacterial Killing and Immune Modulation

Abstract The presence of drug resistance and extracellular matrix protection in biofilms makes it increasingly difficult to control bacterial infections using antibiotics. Therefore, there is an urgent need to develop new non‐antibiotic approaches to eradicate drug‐resistant bacterial infections. Here, a bimetal‐phenolic framework (Que‐Fe‐CeMPF) is constructed by direct self‐assembly of coordinated Fe 3+ and Ce 4+ ions with the polyphenol quercetin (Que). Que‐Fe‐CeMPF enhanced hydroxyl radical (·OH) generation, particularly in an acidic environment and presence of H 2 O 2, compared with single metal‐phenolic frameworks (Que‐FeMPF and Que‐CeMPF). · OH damaged bacterial cell walls, resulting in intracellular protein loss and bacterial cell death. Additionally, Que‐Fe‐CeMPF effectively dispersed biofilms by degrading matrix eDNA, allowing easier ·OH penetration, resulting in higher killing efficiency compared to Que‐FeMPF and Que‐CeMPF. Que‐Fe‐CeMPF stimulated macrophages to adopt an M2‐like phenotype, suppressing excessive immune activation and promoting tissue repair at the infection site. As a combined effect of bacterial killing, biofilm degradation, and immune‐modulation, the infectious pneumonia caused by Pseudomonas aeruginosa in mice is more effectively eradicated by Que‐Fe‐CeMPF than by free quercetin or the antibiotic ciprofloxacin. Moreover, Que‐Fe‐CeMPF is less prone to resistance development in pathogens compared to ciprofloxacin. Thus, Que‐Fe‐CeMPF is a promising non‐antibiotic antimicrobial agent with multimodal activity for controlling drug‐resistant bacterial infections.