Lung-targeted hepatocyte growth factor mRNA restores alveolar structure in experimental emphysema

Emphysema, a major component of COPD characterised by progressive alveolar destruction, lacks effective medical therapies. Hepatocyte growth factor (HGF) possesses potent regenerative functions, but its therapeutic potential remains unrealised due to challenges in achieving targeted delivery and sustained lung expression.

We first assessed associations between HGF expression and emphysema severity using human datasets, lung tissue, and both elastase-induced and cigarette-smoke-induced murine models. We repurposed a clinical-stage SM102 lipid nanoparticles platform to deliver human HGF mRNA in murine models, evaluating therapeutic efficacy via intratracheal instillation in the elastase model. After optimising nebulisation, we assessed efficacy in the cigarette-smoke model. We investigated underlying mechanisms via single-cell RNA sequencing (scRNA-seq), which we validated in patient-derived lung organoids.

HGF expression displayed a biphasic pattern across the emphysema spectrum, with upregulation in milder disease states and marked reduction in advanced emphysema. Intratracheal delivery of HGF mRNA lipid nanoparticles restored lung function and attenuated alveolar destruction in the elastase model. Nebulised 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.

This study provides proof-of-concept evidence for a therapeutic strategy for emphysema. Using a clinical-stage lipid nanoparticle platform, we demonstrate that HGF mRNA therapy is effective via both direct instillation and optimised nebulisation, prompting structural and functional recovery by activating endogenous repair pathways in AT2 cells.