Mannosylated MOF Encapsulated in Lactobacillus Biofilm for Dual‐Targeting Intervention Against Mammalian Escherichia coli Infections

Abstract Pathogenic bacterial infections pose a major concern, especially concerning mammalian enteritis and diarrhea. Compared to conventional antibiotic intervention, metal–organic frameworks (MOFs) exhibit superior antibacterial properties and lower cytotoxicity, demonstrating great promise in the treatment of pathogen‐induced diarrhea. However, the achievement of their precise targeted delivery is still a significant challenge. Herein, a novel precision nano‐system with a dual‐targeting approach for treating intestinal infections caused by Escherichia coli (E. coli) is designed. First, Zn‐MOF was synthesized based on ZnO, which possessed enhanced elimination of planktonic bacteria and biofilms. Through mannosylation, Zn‐MOF@Man specifically recognized the FimH pili of E. coli, leading to its aggregation and subsequent eradication. Second, guided by whole genome sequencing, the encapsulation of Lactobacillus biofilm exertd immunomodulatory function, overcomed challenges related to intestinal targeting, and facilitated sustained drug release. Furthermore, Zn‐MOF@Man/LRB maintaind microbiota equilibrium and promoted stem cell differentiation and barrier stability, ensuring consistent anti‐diarrheal and anti‐inflammatory efficacy in mice, piglets, and humans. This approach represents a novel dual‐targeting antimicrobial strategy, combining probiotic biofilms and E. coli‐oriented delivery, advancing safe and effective treatment that restores intestinal homeostasis for potential applications in both human medicine and animal husbandry.