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Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium
Author(s) -
Patel Asha Kumari,
Kaczmarek James C.,
Bose Suman,
Kauffman Kevin J.,
Mir Faryal,
Heartlein Michael W.,
DeRosa Frank,
Langer Robert,
Anderson Daniel G.
Publication year - 2019
Publication title -
advanced materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.707
H-Index - 527
eISSN - 1521-4095
pISSN - 0935-9648
DOI - 10.1002/adma.201805116
Subject(s) - inhalation , lung , messenger rna , nucleic acid , transfection , luciferase , distribution (mathematics) , in vitro , epithelium , population , pharmacology , biology , materials science , pathology , medicine , biochemistry , anatomy , gene , mathematical analysis , mathematics , environmental health
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.