Enzyme‐Activated Core–Shell Drug Co‐Crystal Nanoparticles for Targeted Salmonella Clearance and Gut Microbiome Restoration

Abstract

Salmonella Typhimurium—a gut‐colonizing pathogen that invades mucosa and triggers colitis—remains clinically challenging due to host barriers limiting oral antibiotic efficacy. To address this issue, an innovative co‐crystal nanoparticle platform is developed for targeted therapy. This platform consists of PC@Kana@TA nanoparticles (PC@Kana@TA NPs), synthesized through a simple, cost‐effective, and scalable process involving two key steps: 1) self‐assembly of tannic acid (TA) with kanamycin (Kana) to form the antimicrobial core Kana@TA nanoparticles (Kana@TA NPs), enhancing drug stability and bactericidal efficacy; and 2) subsequent coating of Kana@TA NPs with mixed pectin–chitosan (PC) to generate the final PC@Kana@TA NPs. This dual‐layer coating strategy not only provides gastric acid resistance but also enables pectinase‐responsive release in the intestinal tract, thereby significantly improving oral bioavailability compared to conventional formulations. In vitro, Kana@TA NPs exhibit above 70% intracellular Salmonella clearance rate in both the RAW264.7 and Caco‐2 cells. Animal experiments revealed that PC@Kana@TA NPs achieved a 5‐log reduction in luminal Salmonella, with inflammatory cytokine levels nearly returned to baseline. Notably, the relatively beneficial gut bacteria abundance is 30.53% higher than the Kana group. This strategy presents a versatile strategy for nano‐enabled intracellular infection therapies, unlocking new opportunities for drug repurposing and optimization.