Oligo(serine ester) Charge-Altering Releasable Transporters: Organocatalytic Ring-Opening Polymerization and their Use for in Vitro and in Vivo mRNA Delivery

RNA technology is transforming life science research and medicine, but many applications are limited by the accessibility, cost, efficacy, and tolerability of delivery systems. Here we report the first members of a new class of dynamic RNA delivery vectors, oligo­(serine ester)-based charge-altering...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2019-05, Vol.141 (21), p.8416-8421
Main Authors: Benner, Nancy L, McClellan, Rebecca L, Turlington, Christopher R, Haabeth, Ole A. W, Waymouth, Robert M, Wender, Paul A
Format: Article
Language:English
Subjects:
Animals
Anions - chemistry
Esters - administration & dosage
Esters - chemistry
Female
Genetic Vectors - administration & dosage
Genetic Vectors - chemistry
HeLa Cells
Humans
Luciferases - chemistry
Luciferases - metabolism
Mice
Mice, Inbred BALB C
Molecular Structure
Polymerization
Repressor Proteins - chemistry
Repressor Proteins - metabolism
RNA, Messenger - administration & dosage
RNA, Messenger - genetics
RNA, Messenger - metabolism
Serine - administration & dosage
Serine - chemistry
Spleen - chemistry
Spleen - metabolism
Thiourea - chemistry
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Summary:RNA technology is transforming life science research and medicine, but many applications are limited by the accessibility, cost, efficacy, and tolerability of delivery systems. Here we report the first members of a new class of dynamic RNA delivery vectors, oligo­(serine ester)-based charge-altering releasable transporters (Ser-CARTs). Composed of lipid-containing oligocarbonates and cationic oligo­(serine esters), Ser-CARTs are readily prepared (one flask) by a mild ring-opening polymerization using thiourea anions and, upon simple mixing with mRNA, readily form complexes that degrade to neutral serine-based products, efficiently releasing their mRNA cargo. mRNA/Ser-CART transfection efficiencies of >95% are achieved in vitro. Intramuscular or intravenous (iv) injections of mRNA/Ser-CARTs into living mice result in in vivo expression of a luciferase reporter protein, with spleen localization observed after iv injection.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.9b03154