Lung-Targeted HGF mRNA Restores Alveolar Structure in Experimental Emphysema

BACKGROUND: Emphysema, a major component of chronic obstructive pulmonary disease (COPD) characterized by progressive alveolar destruction, lacks effective medical therapies. Hepatocyte growth factor (HGF) possesses potent regenerative functions, but its therapeutic potential remains unrealized due to challenges in achieving targeted delivery and sustained lung expression. METHODS: single-cell RNA sequencing (scRNA-seq), which we validated in patient-derived lung organoids. RESULTS: HGF expression displayed a biphasic pattern across the emphysema spectrum, with upregulation in milder disease states and marked reduction in advanced emphysema. i.t. delivery of HGF mRNA LNPs restored lung function and attenuated alveolar destruction in the elastase model. Nebulized delivery achieved efficient pulmonary distribution and demonstrated comparable therapeutic efficacy in the cigarette-smoke model, including improved lung function, reduced inflammation, and decreased apoptosis. scRNA-seq analysis detected enhanced alveolar type II (AT2) cell proliferation and differentiation in the elastase model and human organoids. CONCLUSION: both direct instillation and optimized nebulization, prompting structural and functional recovery by activating endogenous repair pathways in AT2 cells.