An antibiotic-free platform for eliminating persistent Helicobacter pylori infection without disrupting gut microbiota

Abstract

<i>Helicobacter pylori</i> (<i>H. pylori)</i> infection remains the leading cause of gastric adenocarcinoma, and its eradication primarily relies on the prolonged and intensive use of two antibiotics. However, antibiotic resistance has become a compelling health issue, leading to <i>H. pylori</i> eradication treatment failure worldwide. Additionally, the powerlessness of antibiotics against biofilms, as well as intracellular <i>H. pylori</i> and the long-term damage of antibiotics to the intestinal microbiota, have also created an urgent demand for antibiotic-free approaches. Herein, we describe an antibiotic-free, multifunctional copper-organic framework (HKUST-1) platform encased in a lipid layer comprising phosphatidic acid (PA), rhamnolipid (RHL), and cholesterol (CHOL), enveloped in chitosan (CS), and loaded in an ascorbyl palmitate (AP) hydrogel: AP@CS@Lip@HKUST-1. This platform targets inflammatory sites where <i>H. pylori</i> aggregates through electrostatic attraction. Then, hydrolysis by matrix metalloproteinases (MMPs) releases CS-encased nanoparticles, disrupting bacterial urease activity and membrane integrity. Additionally, RHL disperses biofilms, while PA promotes lysosomal acidification and activates host autophagy, enabling clearance of intracellular <i>H. pylori</i>. Furthermore, AP@CS@Lip@HKUST-1 alleviates inflammation and enhances mucosal repair through delayed Cu²⁺ release while preserving the intestinal microbiota. Collectively, this platform presents an advanced therapeutic strategy for eradicating persistent <i>H. pylori</i> infection without inducing drug resistance.