Selective ORgan-targeting lipid nanoparticles deliver SMAD7 mRNA to fibrotic lungs and attenuate pulmonary fibrosis.

Abstract

Fibroblast activation and differentiation into myofibroblasts drive excessive extracellular matrix deposition and irreversible scarring in pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF), underscoring the need for therapies that directly target fibroblast activation. Here, we apply engineered lung-targeting Selective ORgan-Targeting (SORT) lipid nanoparticles for intravenous RNA delivery to fibrotic lungs. In a preclinical model of pulmonary fibrosis, engineered SORT LNPs achieved functional mRNA delivery in approximately 20% of CD45-CD31-EpCAM-Thy1.2+ mesenchymal cells in fibrotic lungs. Mechanistic studies further supported a contributory role of the vitronectin (Vtn)/vitronectin receptor (VtnR) axis in 1A7B13 Lung SORT LNP uptake. Therapeutic delivery of SMAD7 mRNA inhibited fibroblast activation in human lung fibroblast cultures and attenuated pulmonary fibrosis in vivo, resulting in an approximately 40% reduction in histological collagen deposition and a significant reduction in lung hydroxyproline content. Together, these findings establish engineered lung-enriched SORT LNPs as a platform for systemic RNA delivery to fibrotic lungs, including disease-relevant mesenchymal populations, and demonstrate their potential for RNA-based anti-fibrotic therapy.

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