Engineered Lipid Nanoparticles for the Treatment of Pulmonary Fibrosis by Regulating Epithelial‐Mesenchymal Transition in the Lungs

Abstract Pulmonary fibrosis is a chronic and irreversible lung disease with limited therapeutic regimens. Advances in elucidating the pathophysiological mechanism and discovering novel therapeutic interventions are still in urgent need. Here, the engineered lipid nanoparticles (LNPs) are developed for delivering RNA therapeutics to the lungs. Three different types of LNPs (native, cationic, and ligand incorporated) are optimized to facilitate the pulmonary delivery of RNAs. Among them, the mannose incorporated LNPs (Mannose LNPs) outperform the others and show efficient delivery of siRNAs down‐regulating the epithelial‐mesenchymal transition (EMT) associated protein, G2 and S phase‐expressed protein 1 (GTSE1). Treatment with the mannose LNPs confirms a significant decrease in collagen accumulation and EMT‐related proteins in the fibrosis animal models and provides functional recovery from pulmonary fibrosis. This approach demonstrates that engineered LNPs can facilitate the delivery of RNA therapeutics to the lungs and potentially open a new regimen of treatment for pulmonary fibrosis.