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To address this issue, an innovative co\u2010crystal nanoparticle platform is developed for targeted therapy. This platform consists of PC@Kana@TA nanoparticles (PC@Kana@TA NPs), synthesized through a simple, cost\u2010effective, and scalable process involving two key steps: 1) self\u2010assembly 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\u2013chitosan (PC) to generate the final PC@Kana@TA NPs. This dual\u2010layer coating strategy not only provides gastric acid resistance but also enables pectinase\u2010responsive 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\u20102 cells. Animal experiments revealed that PC@Kana@TA NPs achieved a 5\u2010log 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\u2010enabled intracellular infection therapies, unlocking new opportunities for drug repurposing and optimization.\n                  <\/jats:p>","DOI":"10.1002\/smll.202504914","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T12:26:09Z","timestamp":1760444769000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enzyme\u2010Activated Core\u2013Shell Drug Co\u2010Crystal Nanoparticles for Targeted\n                    <i>Salmonella<\/i>\n                    Clearance and Gut Microbiome Restoration"],"prefix":"10.1002","volume":"21","author":[{"given":"Siying","family":"Huang","sequence":"first","affiliation":[{"name":"Sanya Institute of China Agricultural University  Sanya 572025 P. R. 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