Chitosan–hyaluronic acid nanoparticles with time-dependent mucoadhesive and mucus penetrating behaviour to overcome pathological lung mucus

Abstract

Bacterial infections are a major complication in pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS), aggravated by multidrug-resistant bacteria and the presence of pathological mucus that limits antibiotics efficacy. To address this challenge, drug-free chitosan/hyaluronic acid (CS/HA) nanoparticles were developed through a one-step ionic gelation method. By modulating the CS/HA ratio and HA molecular weight, stable, spherical nanoparticles with sizes ranging from 75 to 210 nm and positive ζ-potentials between +22 and +34 mV were obtained. FTIR confirmed electrostatic stabilization. The nanoparticles exhibited a unique time-dependent behavior: initial adherence to pathological mucus for local retention, followed by a hydration-driven surface rearrangement enabling mucus barrier penetration. This sequential mucoadhesive-to-mucus-penetrating transition is reported for the first time for a drug-free carbohydrate network. Biological assays demonstrated excellent biocompatibility with healthy and diseased human lung fibroblasts (HLF, HLF COPD and A549), alongside significant antioxidant activity. Moreover, the nanoparticles exerted dose-dependent, intrinsic antimicrobial effects against major respiratory pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa. Overall, by engineering a dynamically adaptive interface, this work crucially resolves the historical trade-off between mucosal retention and diffusion, establishing a promising nanotherapeutic strategy for combating multidrug-resistant pulmonary infections directly at the mucus site.