Eradicating Helicobacter pylori and reversing precancerous intestinal metaplasia by gastric epithelial cells-localizable oral nanomedicines

The ability to treat Helicobacter pylori (H. pylori) infection and eliminate its associated gastric cancer risk is highly desirable but has proven to be extremely difficult. In this study, pilot proteomic screening of clinical gastric mucosal samples suggested a progressive decline in Sirtuin 1 abundance along the H. pylori-associated pathological cascade. Based on these findings, gastric epithelial cells-localizable oral nanomedicines (GLONs) are developed, whereby H. pylori eradication and reversal of precancerous intestinal metaplasia (IM) are simultaneously achieved via Sirtuin 1 restoration. GLONs are constructed by coating resveratrol, lactoferrin, and disulfide modified-fucoidan (DFu) co-assembled nanoparticles (RLF) with engineered mucin-overexpressing gastric epithelial cell membranes. The shell of GLONs resists gastric acid, enhances mucus penetration and epithelial cells uptake. After internalization, DFu undergoes oxidative destabilization in the H₂O₂-enriched infectious microenvironment induced by H. pylori, thereby triggering RLF core dissociation and subsequent component release. The resveratrol restored H. pylori infection-induced impairment of Sirtuin 1, thereby activating autophagy. Meanwhile, lactoferrin promoted antimicrobial peptide production and synergized with fucoidan-mediated enhancement of antigen presentation, ultimately enabling the clearance of both intracellular and extracellular H. pylori. In metaplastic gastric cells, Sirtuin 1 repairs damaged DNA, and inhibits malignant proliferation. In mouse models, under the tested 7-day regimen, GLONs produced greater reductions in gastric H. pylori burden and more pronounced improvements in IM-related phenotypes than the abbreviated triple-therapy. GLONs represent an innovative and highly efficient therapeutic platform for H. pylori infection and its complications.