Inhalable dexamethasone-loaded zwitterionic nanomicelles enabling effective penetration of the mucus barrier for acute lung injury treatment

Acute Lung Injury (ALI) is a clinical syndrome associated with various respiratory diseases and injuries. While inhalable drug delivery systems offer the advantage of direct pulmonary targeting and reduced systemic toxicity, their therapeutic efficacy is frequently compromised by the tracheobronchial mucus barrier. To address this limitation, we developed PCL-ss-PSBMA, a novel nanocarrier engineered to overcome the constraints of conventional micelle platforms, which typically depend on either hydrophilic coatings or single-response mechanisms. By integrating zwitterionic groups and disulfide bonds in a dual-functional design, PCL-ss-PSBMA achieves synergistic optimization of mucus barrier penetration and glutathione (GSH)-triggered drug release. In addition, the nanocarrier also exhibits excellent biocompatibility, further ensuring its safety in therapeutic applications. In an ALI murine model, PCL-ss-PSBMA@DEX markedly improved the delivery efficiency and utilization rate of dexamethasone (DEX) through its dual mechanisms of mucus penetration and stimulus-responsive drug release. This design not only enhances the deposition of the drug in the lungs but also achieves efficient treatment of ALI by precisely controlling drug release, demonstrating its potential as an advanced strategy for treating respiratory diseases.