Biodegradable Acid‐Responsive Nanocarrier for Enhanced Antibiotic Therapy Against Drug‐Resistant <i>Helicobacter Pylori</i> via Urease Inhibition

Abstract Metal ion‐based inhibition of urease activity is a promising strategy for treating Helicobacter pylori ( H. pylori ) infections. However, the challenges of safe delivery and reducing cytotoxicity persist. In this study, an innovative nanocarrier capable of acid‐responsive release of Ag + and antibiotics is developed, with complete degradation after treatment. Mesoporous organosilica nanoparticle (MON) is encapsulated with hyaluronic acid (HA) to prevent drug leakage and further coated with bacterial outer membrane vesicle (OMV) from Escherichia coli Nissle 1917, creating a nanocarrier with cell‐protective capabilities. Ag + and antibiotic clarithromycin (CLR) are incorporated into the nanocarrier to form CLR‐Ag + @MON@HA@OMV (CAMO), designed for the targeted treatment of gastric H. pylori infection. The HA encapsulation ensures acid‐responsive release of CLR and Ag + in the stomach, preventing premature release at non‐inflammatory sites. There is a potential for Ag⁺ in CAMO to replace Ni 2 ⁺ at the active site of urease, enhancing the bactericidal effect of CLR through urease inhibition. Furthermore, the OMV provides additional cytoprotection, mitigating cell damage and inflammation response induced by the H. pylori infection. This study introduces a safe and effective nanocarrier that eradicates H. pylori and alleviates gastric inflammation.