A softness zwitterionic micelles efficiently deliver inhaled nintedanib by enhancing airway mucus penetration.

Inhalation therapy shows great potential for treating idiopathic pulmonary fibrosis (IPF), but airway mucus imposes strong adhesive and steric barriers to drug delivery. Compared with other types of micelles, our results demonstrated that amphiphilic micelles formed by DSPE-PCB [carboxybetaine polymer conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DB)] exhibited superior physicochemical properties for mucus penetration. Furthermore, we found that incorporating a conformationally adaptive azobenzene (Azo) intermediate into DB further enhanced this effect by modulating mechanical properties of micelle. By tuning DB/DAB ratios during self-assembly, we generated a micelle library with adjustable deformability (1- to 40-fold). The enhanced mucus penetration ability led to a nearly fourfold reduction in the retention time of DSPE-Azo-PCB (DAB) micelles in respiratory mucus, significantly increasing drug accumulation in lung tissue and reducing irritation to the respiratory tract. This study integrates both the physicochemical and mechanical properties of micelles to optimize mucus penetration, offering previously unidentified strategies for the development of inhalation formulations.