Scheme 1.

Delivery and light-activation of antisense agents containing caging groups conjugated with cell-penetrating peptides. PNVOM-caged thymidine nucleotides are site-specifically incorporated into antisense agents and are bioconjugated with azido-CPPs. The CPP-caged antisense agent conjugates are (1) simply added to the cell culture media and (2) are taken up by mammalian cells, but remain inactive due to the presence of the caging groups. (3) UV irradiation triggers decaging, cleaving the CPPs from the antisense agent and inducing sequence-specific mRNA binding. This leads to (4) the silencing of gene expression either by blocking the ribosome or by inducing RNase H-mediated mRNA degradation.