Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly a...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-01, Vol.114 (4), p.E448-E456
Main Authors: McKinlay, Colin J., Vargas, Jessica R., Blake, Timothy R., Hardy, Jonathan W., Kanada, Masamitsu, Contag, Christopher H., Wender, Paul A., Waymouth, Robert M.
Format: Article
Language:English
Subjects:
Animals
BASIC BIOLOGICAL SCIENCES
Biocompatible Materials - administration & dosage
Biodegradable materials
Biological Sciences
Carbocyanines
Cell culture
Cell Line
Cell Line, Tumor
cell-penetrating
Cells, Cultured
Female
gene therapy
Gene Transfer Techniques
Green Fluorescent Proteins - genetics
Humans
Medical treatment
Mesenchymal Stem Cells - metabolism
Mice, Inbred BALB C
nanoparticle
organocatalysis
Physical Sciences
PNAS Plus
Proteins
Ribonucleic acid
RNA
RNA, Messenger - administration & dosage
stimuli-responsive
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Summary:Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here we report the step-economical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1614193114