Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium
Name
AKPatel2019AdvMat.pdf
Description
Accepted version
Size
1.08 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Patel, Asha Kumari
Kaczmarek, James Cliff
Bose, Suman
Kauffman, Kevin John
Mir, Faryal
Heartlein, Michael W.
DeRosa, Frank
Langer, Robert S
Anderson, Daniel Griffith
Date Issued
January 2019
Journal
Advanced Materials
Publisher
Wiley
Citation
Patel, Asha Kumari et al. "Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium." Advanced Materials 31, 8 (February 2019): 1805116 © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Version
Author's final manuscript
Abstract
Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic-acid-based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal and dose-dependent control of encoded protein expression. Inhaled delivery of IVT-mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g −1 of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE-mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT-mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium. Keywords: biomaterials; gene delivery; inhalation; messenger RNA; topology
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1002/adma.201805116
