Publication date: Jan 25, 2025

Exemplified by successful use in COVID-19 vaccination, delivery of modified mRNA encapsulated in lipid nanoparticles provides a framework for treating various genetic and acquired disorders. However, lipid nanoparticles that can deliver mRNA into specific lung cell types have not yet been established. Here, we sought whether poly((R)-amino ester)s (PBAE) or PEGylated PBAE (PBAE-PEG) in combination with 4A3-SC8/DOPE/cholesterol/DOTAP lipid nanoparticles (LNP) could deliver mRNA into different types of lung cells in vivo. PBAE-PEG/LNP was similar to Lipofectamine MessengerMAX followed by PBAE/LNP for mRNA transfection efficiency in HEK293T cells in vitro. PBAE-PEG/LNP administered by intravenous (IV) injection achieved 55% mRNA transfection efficiency into lung endothelial cells while PBAE-PEG/LNP administered by intratracheal (IT) injection achieved 73% efficiency into lung alveolar type II (ATII) epithelial cells in mice in vivo. PBAE/LNP administered by IT injection were superior for specific delivery into lung airway club epithelial cells compared to PBAE-PEG/LNP. Lipofectamine MessengerMAX was inactive in vivo. 5-methoxyuridine modified (5moU) mRNA was more efficient than unmodified mRNA in vivo but not in vitro. Our findings indicate that PBAE-PEG/LNP and PBAE/LNP can transfect multiple lung cell types in vivo, which can be applied for gene therapy targeting genetic lung diseases.

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Original Article