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Adv Mater. 2019 Jan 4:e1805116. doi: 10.1002/adma.201805116. [Epub ahead of print]

Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
2
Division of Cancer and Stem Cells, School of Medicine, and Division of Advanced Materials and Healthcare Technologies, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK.
3
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
4
TranslateBio, Lexington, MA, 02421, USA.
5
Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
6
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

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

PMID:
30609147
DOI:
10.1002/adma.201805116

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