Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing

The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CR...

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Bibliographic Details
Published in:	Nature biotechnology Vol. 41; no. 10; pp. 1410 - 1415
Main Authors:	Li, Bowen, Manan, Rajith Singh, Liang, Shun-Qing, Gordon, Akiva, Jiang, Allen, Varley, Andrew, Gao, Guangping, Langer, Robert, Xue, Wen, Anderson, Daniel
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-10-2023 Nature Publishing Group
Subjects:	631/61/2300 631/61/2300/1514 631/61/391 Agriculture Biodegradation Bioinformatics Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology Brief Communication Combinatorial analysis Congenital diseases CRISPR Editing Epithelium Gene therapy Genetic modification Genome editing Genomes Life Sciences Lipids Lung diseases Medical research mRNA Nanoparticles Physiology Proteins Trachea Vectors (Biology)
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Summary:	The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CRISPR–Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases. A high-throughput screen improves lipid nanoparticle delivery of gene editors in the lung.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions B.L., R.S.M. and S.L. conceived the project and wrote the manuscript with input from all the authors. B.L. and R.S.M. designed the combinatorial lipid library. B.L., R.S.M., S.L., A.G., and A. J. performed experiments and analyzed data. B.L., R.S.M., and S.L. wrote the manuscript. B.L., S.L., A.V., W.X. and D.G.A. discussed the results and edited the manuscript. G.G., R.L., W.X. and D.G.A. acquired funding and supervised the project.
ISSN:	1087-0156 1546-1696
DOI:	10.1038/s41587-023-01679-x