Eradicating Helicobacter Pylori with a Multifunctional Trojan Horse Nanoplatform Armored with β‐Cyclodextrin

ABSTRACT Conventional therapy for Helicobacter pylori ( H. pylori ) is often compromised by host autophagy dysfunction. Host‐directed therapy (HDT) presents a viable solution; however, its efficacy is hindered by biological barriers and the difficulty in targeting infected cells. Herein, we developed BPI‐CD‐L CR , a self‐propelled “Trojan Horse” nanoplatform functionalized with bacterial‐targeting peptide (B‐mBPI) and urease‐powered motor (TPGS‐β‐CD@Urease), in which TPGS‐β‐cyclodextrin (TPGS‐β‐CD) plays multiple critical roles from drug delivery to autophagy modulation. Initially, TPGS‐β‐CD maximizes urease motor activity against the gastric environment by forming a dynamic complex with urease, thereby powering active propulsion for deep mucus penetration. Upon reaching the infection site, BPI‐CD‐L CR employs a Trojan horse mechanism by tracking bacteria and mediates opsonophagocytosis by macrophages. Meantime, TPGS‐β‐CD outside facilitates BPI‐CD‐L CR phagocytosis by increasing the membrane fluidity of infected macrophage via cholesterol extraction. Intracellularly, BPI‐CD‐L CR modulates the autophagy pathway by promoting autophagosome‐lysosome fusion with the aid of TPGS‐β‐CD and restoring lysosomal function through resveratrol (Res), thereby reactivating the clearance of intracellular bacteria. In the murine infection model, BPI‐CD‐L CR achieved a remarkable 33‐fold reduction in gastric bacterial load compared to antibiotic‐based triple therapy. Overall, this platform represents a nanoengineered delivery strategy for intractable infections, providing a promising solution for guiding HDT to achieve on‐demand antimicrobial activation within infected cells.