Disrupting Helicobacter pylori Iron Homeostasis With Bismuth Nanodrug‐Mediated Nutritional Trap for Targeted Gastric Infection Therapy

Helicobacter pylori ( H. pylori ) is a leading cause of gastric cancer, but current antibiotic‐based therapies face challenges like low eradication rates, high recurrence, and intestinal flora disruption. Iron is critical for H. pylori ’s survival and pathogenicity, as the bacterium relies on maintaining iron homeostasis for normal proliferation, metabolism, and colonization of the stomach. Inspired by this, we propose a “nutritional trap” strategy, using bismuth as “fake iron” to trick the H. pylori ’s iron‐uptake system, triggering iron starvation. We then developed a bismuth‐based nanodrug (Bi‐TP@FU, TBF) modified with tea polyphenols and fucoidan for enhanced H. pylori targeting and gastric mucosal penetration. TBF targets and adheres to the surface of H. pylori by binding to the BabA protein, then induces iron starvation and metabolic disorders through competition between bismuth and iron, ultimately killing multidrug‐resistant strains without inducing resistance. Interestingly, TBF selectively eliminated pathogens while preserving probiotics, thus maintaining intestinal flora balance, which is superior to quadruple therapy. This novel oral TBF, which relies on a nutritional trap‐based bactericidal strategy, offers a new option for antibiotic alternative therapy of bacterial infections. A “nutritional trap” strategy centered on disrupting bacterial iron homeostasis is proposed. The synthesized Bi‐TP@FU (TBF) can target Helicobacter pylori , interfere with the bacterial iron uptake and utilization processes to disrupt its iron homeostasis, induce bacterial death, and meanwhile preserve the balance of the intestinal flora. This finding further offers a novel approach for antibiotic‐alternative therapies against Helicobacter pylori infection.