In order to achieve light-control of oligonucleotide function, we are developing synthetic approaches to monomeric building blocks for oligonucleotides that contain caged nucleobases. The caging groups block Watson-Crick hydrogen-bonding and completely prevent oligonucleotide duplex formation, until removed through a brief exposure to UV light. When the caging groups are installed on antisense oligonucleotides, they enable optochemical control of ON to OFF and OFF to ON switching of gene expression with unprecedented spatial and temporal resolution in human cells, tissues, and multicellular organisms. When bioconjugated to delivery agents, the caging groups enable targeted delivery of oligonucleotides in addition to spatio-temporal control.
