Cellular Delivery and Photochemical Activation of
Antisense Agents through a Nucleobase Caging Strategy
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Abstract
Antisense
oligonucleotides are powerful tools to regulate gene
expression in cells and model organisms. However, a transfection or
microinjection is typically needed for efficient delivery of the antisense
agent. We report the conjugation of multiple HIV TAT peptides to a
hairpin-protected antisense agent through a light-cleavable nucleobase
caging group. This conjugation allows for the facile delivery of the
antisense agent without a transfection reagent, and photochemical
activation offers precise control over gene expression. The developed
approach is highly modular, as demonstrated by the conjugation of
folic acid to the caged antisense agent. This enabled targeted cell
delivery through cell-surface folate receptors followed by photochemical
triggering of antisense activity. Importantly, the presented strategy
delivers native oligonucleotides after light-activation, devoid of
any delivery functionalities or modifications that could otherwise
impair their antisense activity