Pulmonary Surfactant Nanoparticles for Lung-Targeted and Dose-Efficient Delivery

Although pulmonary drug delivery enables lung-targeted therapy, its clinical efficacy is often limited by inflammation, heterogeneous deposition, and physiological barriers such as mucociliary clearance and phagocytic uptake. Here, we report a biomimetic platform based on pulmonary surfactant nanoparticles (PS_NPs) that preserves native surfactant proteins and biophysical functionality, resulting in enhanced pulmonary delivery. Microfluidic synthesis yielded highly uniform PS_NPs with improved encapsulation efficiency and colloidal stability, while markedly increasing surfactant protein retention from 33% using conventional extrusion to 95% via microfluidics, corresponding to a 2.4-fold improvement. Functionally, PS_NPs exhibited superior interfacial activity compared to lipid-only liposomes, increasing surface pressure from 5-10 mN/m to 25-30 mN/m, and achieved an approximately 80-fold enhancement in alveolar cellular uptake. In vitro, nintedanib-loaded PS_NPs significantly reduced fibroblast migration, proliferation, collagen deposition, and TGF-β secretion relative to free drug and control formulations. In vivo, PS_NPs demonstrated high pulmonary retention (95% injected dose per gram of lung tissue), efficient penetration into fibrotic regions, and minimal off-target accumulation in the liver (0.5%). Therapeutic efficacy was confirmed in a bleomycin-induced pulmonary fibrosis model, where PS_NPs improved lung function and restored tissue architecture at doses as low as 0.5 mg/kg. Collectively, these results establish PS_NPs as a robust lung-targeted nanotherapeutic platform, where microfluidic synthesis enables enhanced biomimicry, improved protein preservation, and superior therapeutic performance compared to conventional fabrication methods.