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

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.