Fluorinated Liposome-Coated Coacervates: Low-Energy Interfaces for Mucus Penetration and Pulmonary Delivery in Acute Respiratory Distress Syndrome

Pulmonary inhalation offers a direct route for drug delivery in acute respiratory distress syndrome (ARDS). However, the efficacy of inhaled therapeutics is often limited by poor stability during nebulization and inability to penetrate the mucus layer. This study developed an inhalation delivery system using fluorinated liposome-coated coacervates (PD-Coac@LipF) for the combined delivery of prednisolone sodium phosphate (PSP) and deoxyribonuclease I (DNase I) to treat ARDS. The coacervate core, formed by liquid–liquid phase separation, could efficiently enrich both PSP and macromolecular DNase I and protect their activity during nebulization. Surface modification with fluorinated liposomes enhanced mucus penetration due to the low surface energy of fluorocarbon chains, enabling rapid diffusion through the pulmonary mucus barrier. Upon deposition in the inflammatory alveolar microenvironment, PD-Coac@LipF adhered to neutrophil extracellular traps (NETs) and facilitated DNase I-mediated degradation, whereas PSP concurrently drived macrophage repolarization toward the anti-inflammatory M2 phenotype. PD-Coac@LipF demonstrated to reduce reactive oxygen species, downregulate pro-inflammatory cytokines, decrease neutrophil infiltration, and alleviate lung injury in ARDS mice. The system also exhibited excellent lung retention and distribution, offering a promising strategy for targeted, efficient, and stable pulmonary inhalation therapy against diseases.