Combinatorial development of nebulized mRNA delivery formulations for the lungs
Name
nihms-1949779.pdf
Description
Accepted version
Size
2.29 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Jiang, Allen Y
Witten, Jacob
Raji, Idris O
Eweje, Feyisayo
MacIsaac, Corina
Meng, Sabrina
Oladimeji, Favour A
Hu, Yizong
Manan, Rajith S
Langer, Robert
Date Issued
November 20, 2023
Journal
Nature Nanotechnology
Publisher
Springer Science and Business Media LLC
Citation
Jiang, A.Y., Witten, J., Raji, I.O. et al. Combinatorial development of nebulized mRNA delivery formulations for the lungs. Nat. Nanotechnol. 19, 364–375 (2024).
Version
Author's final manuscript
Abstract
Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air–liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant improvement in lung mRNA delivery over current state-of-the-art LNPs and polymeric nanoparticles.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biological Engineering
Harvard University--MIT Division of Health Sciences and Technology
Institute for Medical Engineering and Science
Terms of Use
Creative Commons Attribution-Noncommercial-ShareAlike
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DOI of Published Version
https://doi.org/10.1038/s41565-023-01548-3
