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

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.