Inhalable Hsa‐miR‐30a‐3p Liposomes Attenuate Pulmonary Fibrosis

Abstract Idiopathic pulmonary fibrosis (IPF) remains an incurable form of interstitial lung disease with sub‐optimal treatments that merely address adverse symptoms or slow fibrotic progression. Here, inhalable hsa‐miR‐30a‐3p‐loaded liposomes (miR‐30a) for the treatment of bleomycin‐induced pulmonary fibrosis in mice are presented. It was previously found that exosomes (Exo) derived from lung spheroid cells are therapeutic in multiple animal models of pulmonary fibrosis and are highly enriched for hsa‐miR‐30a‐3p. The present study investigates this miRNA as a singular factor to treat IPF. Liposomes containing miR‐30a mimic can be delivered to rodents through dry powder inhalation. Inhaled miR‐30a and Exo consistently lead to improved pulmonary function across six consecutive pulmonary function tests and promote de‐differentiation of profibrotic myofibroblasts. The heterogenous composure of Exo also promotes reparative alveolar type I and II cell remodeling and vascular wound healing through broad transforming growth factor‐beta signaling downregulation, while miR‐30a targets myofibroblast de‐differentiation through CNPY2/PERK/DDIT3 signaling. Overall, inhaled miR‐30a represses the epithelial‐mesenchymal transition of myofibroblasts, providing fibrotic attenuation and subsequent improvements in pulmonary function.