Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2019-02-22
Date Acceptance
2018-11-29
Citation
Advanced Materials, 2019, 31 (8), pp.1-7
ISSN
0935-9648
Publisher
Wiley
Start Page
1
End Page
7
Journal / Book Title
Advanced Materials
Volume
31
Issue
8
Copyright Statement
© 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This is the pre-peer reviewed version of the following article, which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1002/adma.201805116.
Identifier
https://onlinelibrary.wiley.com/doi/full/10.1002/adma.201805116
Subjects
Science & Technology
Physical Sciences
Technology
Chemistry, Multidisciplinary
Chemistry, Physical
Nanoscience & Nanotechnology
Materials Science, Multidisciplinary
Physics, Applied
Physics, Condensed Matter
Chemistry
Science & Technology - Other Topics
Materials Science
Physics
biomaterials
gene delivery
inhalation
messenger RNA
topology
GENE DELIVERY
POLY(BETA-AMINO ESTERS)
AEROSOL DELIVERY
CYSTIC-FIBROSIS
MOLECULAR-WEIGHT
IN-VITRO
OPTIMIZATION
EFFICIENCY
COMPLEXES
THERAPY
biomaterials
gene delivery
inhalation
messenger RNA
topology
Administration, Inhalation
Animals
Drug Compounding
Drug Liberation
Epithelial Cells
Female
Gene Transfer Techniques
Genetic Therapy
Hydrogen-Ion Concentration
Luciferases
Lung
Mice
Mice, Inbred C57BL
Models, Animal
Nanoparticles
Polymers
RNA, Messenger
Tissue Distribution
Transfection
Lung
Epithelial Cells
Animals
Mice, Inbred C57BL
Mice
Polymers
Luciferases
RNA, Messenger
Administration, Inhalation
Gene Transfer Techniques
Transfection
Models, Animal
Drug Compounding
Tissue Distribution
Hydrogen-Ion Concentration
Female
Nanoparticles
Genetic Therapy
Drug Liberation
Nanoscience & Nanotechnology
02 Physical Sciences
03 Chemical Sciences
09 Engineering
Publication Status
Published
Article Number
1805116
Date Publish Online
2019-01-04