pH-Programmed Poly(amino acid) Nanoparticles for Mucus-Penetrating and Bacteria-Targeted Eradication of Helicobacter pylori

Abstract The global prevalence of Helicobacter pylori (H. pylori) infection stands in stark contrast to the limited clinical efficacy of antibiotics, primarily attributed to their rapid inactivation under gastric acidity and poor penetration through the gastric mucus barrier. Here, we report a pH-programmed poly(amino acid)-based nanoplatform for the precise eradication of H. pylori. This platform is constructed from poly(amino acid) block copolymers (FAR) incorporating d-aminoalanine side chains and rhamnolipid (RHL) moieties, which self-assemble into amoxicillin-loaded nanoparticles (Am@FAR NPs). Under strongly acidic gastric conditions (pH < 3), Am@FAR NPs undergo extensive protonation, adopting a compact, stabilized configuration that suppresses premature drug release and preserves antibiotic activity. Upon entering the gastric mucus layer (pH ∼ 4–6), partial deprotonation induces surface charge reversal, reducing nonspecific mucin adhesion and facilitating efficient mucus penetration. Cooperative recognition, mediated by RHL and d-aminoalanine residues, enables selective targeting of H. pylori within the mucus niche; here, further local pH elevation (∼6–7) triggers particle swelling and on-site drug release. Consequently, Am@FAR NPs achieve 99.99% eradication efficiency against H. pyloriin vivo, offering a highly effective and biocompatible strategy for the treatment of gastric H. pylori infections.