Abstract

Antibiotics remain the recommended first-line therapy for eradicating Helicobacter pylori infection. However, the harsh gastric physicochemical environment severely limits drug bioavailability, contributing to treatment failure (~10%), gut dysbiosis, and the emergence of antimicrobial resistance. Inspired by H. pylori adhesins binding to gastric epithelial glycan, we developed a biomimetic nanocomposite drug delivery system (BSNG) composed of genetically engineered adhesin-functionalized silk fibroin nanoparticles (BS-NPs) embedded within a fluid silk fibroin hydrogel (FSF-Gel) for targeted anti- H. pylori therapy. BS-NPs exhibit H. pylori -like adhesion to gastric epithelial cells, enabling prolonged gastric retention of over 72 h. FSF-Gel provides conformal coverage of the gastric mucus layer and supports sustained antibiotic release, and prevents acid-induced aggregation of the encapsulated BS-NPs. Upon gastric administration, amoxicillin-loaded BSNG (BSNG@Amo) significantly enhanced both peak drug concentrations and extended therapeutic retention in gastric tissue. In vivo antibacterial studies confirmed that BSNG@Amo achieved superior H. pylori eradication compared to conventional amoxicillin at equivalent doses. Notably, reduced-frequency BSNG@Amo administration maintained therapeutic efficacy while markedly preserving gut microbiota homeostasis. These results highlight BSNG as a precise, long-acting, and microbiota-sparing platform for sustainable gastric antibiotic delivery. Graphical abstract