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. 2025 Mar 5;33(3):1154-1165.
doi: 10.1016/j.ymthe.2025.01.037. Epub 2025 Jan 25.

PBAE-PEG-based lipid nanoparticles for lung cell-specific gene delivery

Bingxin Liu  1 , Yamato Sajiki  2 , Nicole Littlefield  3 , Yongan Hu  3 , William D Stuart  4 , Anusha Sridharan  4 , Xuemei Cui  5 , Matthew E Siefert  6 , Koichi Araki  7 , Assem G Ziady  8 , Donglu Shi  9 , Jeffery A Whitsett  10 , Yutaka Maeda  11
Affiliations

PBAE-PEG-based lipid nanoparticles for lung cell-specific gene delivery

Bingxin Liu et al. Mol Ther. .

Abstract

Exemplified by successful use in COVID-19 vaccination, delivery of modified mRNA encapsulated in lipid nanoparticles (LNPs) provides a framework for treating various genetic and acquired disorders. However, LNPs that can deliver mRNA into specific lung cell types have not yet been established. Here, we sought to determine whether poly(β-amino ester)s (PBAE) or PEGylated PBAE (PBAE-PEG) in combination with 4A3-SC8/DOPE/cholesterol/DOTAP LNPs 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 73% mRNA transfection efficiency into lung endothelial cells, while PBAE-PEG/LNP administered by intratracheal (IT) injection achieved 55% efficiency in 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 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 in gene therapy targeting genetic lung diseases.

Keywords: PBAE-PEG; cell-specific; lipid nanoparticle; lung endothelial cells; lung epithelial cells.

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Conflict of interest statement

Declaration of interests The authors filed an invention disclosure on the combination of PBAE-PEG or PBAE with LNPs.

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References

    1. Nogee L.M., Dunbar A.E., Wert S.E., Askin F., Hamvas A., Whitsett J.A. A Mutation in the Surfactant Protein C Gene Associated with Familial Interstitial Lung Disease. N. Engl. J. Med. 2001;344:573–579. doi: 10.1056/NEJM200102223440805. - DOI - PubMed
    1. Nogee L.M., Garnier G., Dietz H.C., Singer L., Murphy A.M., DeMello D.E., Colten H.R. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J. Clin. Invest. 1994;93:1860–1863. doi: 10.1172/JCI117173. - DOI - PMC - PubMed
    1. Devriendt K., Vanhole C., Matthijs G., de Zegher F. Deletion of Thyroid Transcription Factor-1 Gene in an Infant with Neonatal Thyroid Dysfunction and Respiratory Failure. N. Engl. J. Med. 1998;338:1317–1318. doi: 10.1056/NEJM199804303381817. - DOI - PubMed
    1. Shulenin S., Nogee L.M., Annilo T., Wert S.E., Whitsett J.A., Dean M. ABCA3 Gene Mutations in Newborns with Fatal Surfactant Deficiency. N. Engl. J. Med. 2004;350:1296–1303. doi: 10.1056/NEJMOA032178. - DOI - PubMed
    1. Kerem B., Rommens J.M., Buchanan J.A., Markiewicz D., Cox T.K., Chakravarti A., Buchwald M., Tsui L.C. Identification of the Cystic Fibrosis Gene: Genetic Analysis. Science. 1989;245:1073–1080. doi: 10.1126/SCIENCE.2570460. - DOI - PubMed

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