Abstract

Helicobacter pylori ( H. pylori ) infection disrupts the gastric microenvironment and promotes the development of gastric cancer and other gastrointestinal diseases. Despite the high prevalence of asymptomatic chronic infection and recurrent infections, persistent mucosal injury continues to drive early pathological alterations, including gastric epithelial remodeling and intestinal metaplasia, that may become irreversible beyond a “point of no return”. Although clinical antibiotic-based H. pylori eradication therapies reduce gastric cancer risk, their efficacy markedly diminishes once progressive gastric premalignant lesions developed, and long-term use often causes microbiome dysbiosis and antimicrobial resistance. To address these unmet clinical needs, we developed CurE-gel, an antibiotic-free smart in situ gel with pH- and lipase-cascade responsive drug release. This system enables targeted eradication of H. pylori while simultaneously facilitating gastric niche restoration. Composed of sodium alginate and polyacrylate, CurE-gel exhibits strong gastric mucosal adhesion and precise pH responsiveness. Utilizing the pathophysiological gastric pH gradient (luminal pH 1–2 vs. mucosal pH>4), CurE-gel mediates unidirectional release of its encapsulated nanocapsules (CurE-cap) at damaged mucosal side. Then CurE-cap penetrated the mucus and accumulated at H. pylori colonies, where its polycaprolactone shell is hydrolyzed by bacterial lipase to release curcumin and eugenol. This system achieved: (i) targeted H. pylori eradication via biofilm disruption and virulence suppression; (ii) epithelial barrier protection and pathological progression suppression through virulence translocation inhibition, ROS scavenging, lipid peroxidation reduction and DNA damage mitigation; and (iii) gastric homeostasis restoration by recovery of tight junction proteins and gastric microbiota modulation. In vivo , CurE-gel achieved over 99% H. pylori eradication, reversed gast