PharmaceuticsJul 28, 2026

Improving delivery of therapeutic mRNA to the lungs to prevent lung scarring

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 3, 2026

Abstract

The optimized 50% DOTAP MC3 lipid nanoparticles achieved 94.5% of transgene expression localized to the lungs.

Charge-modified lipid nanoparticles were evaluated for their ability to deliver modRNA specifically to the lungs.
Intravenous administration resulted in robust lung expression and a better safety profile compared to intratracheal delivery.
Pulmonary biodistribution was maintained in fibrotic lungs caused by bleomycin, despite significant tissue remodeling.
Incorporation of microRNA recognition sites enhanced delivery selectivity, reducing liver expression.
In vitro tests showed that the dominant-negative TGF-beta receptor II modRNA effectively inhibited fibrotic activation.

Simplified

Background/Objectives: Pulmonary fibrosis is a progressive and fatal disease characterized by excessive extracellular matrix deposition and irreversible lung remodeling. Although modified mRNA (modRNA) therapeutics offer a promising strategy for regulating disease-driving pathways, effective pulmonary delivery remains challenging due to the inherent liver tropism of conventional lipid nanoparticles (LNPs). This study aimed to establish an optimized platform for lung-selective modRNA delivery and therapeutic screening for pulmonary fibrosis. Methods: A panel of charge-modified LNP formulations was evaluated in vivo for pulmonary tropism following systemic administration of luciferase (Luc) modRNA. Administration routes, biodistribution in healthy and bleomycin (BLM)-induced fibrotic lungs, and endogenous microRNA (miRNA)-mediated de-targeting strategies were assessed. Candidate antifibrotic modRNAs targeting the transforming growth factor-beta (TGF-β) signaling pathway were subsequently evaluated in normal human lung fibroblasts (NHLFs). Results: Among the formulations tested, 50% DOTAP MC3 LNPs demonstrated the most favorable balance of pulmonary transfection, physicochemical properties, and limited off-target expression. Intravenous (IV) administration achieved robust lung expression with a superior safety profile compared with intratracheal (IT) delivery. Importantly, pulmonary biodistribution was preserved in BLM-induced fibrotic lungs despite extensive tissue remodeling. Incorporation of miR-122 recognition sites further enhanced selectivity, resulting in 94.5% of total transgene expression being localized to the lungs while substantially reducing residual hepatic expression. In vitro screening identified dominant-negative TGF-β receptor II (DNTGFBR2) modRNA as a potent inhibitor of TGF-β-induced fibrotic activation, significantly suppressing α-SMA and CTGF expression. Conclusions: These findings establish a comprehensive platform for pulmonary modRNA therapeutic development by integrating lung-selective LNP engineering, optimal systemic delivery, miRNA-mediated de-targeting, and therapeutic payload screening. This strategy provides a foundation for the development of targeted RNA therapies for pulmonary fibrosis and other organ-specific diseases.