Spatiotemporally controlled nuclear translocation of guests in living cells using caged molecular glues as photoactivatable tags

Abstract

© 2019 Journal of Visualized Experiments. The cell nucleus is one of the most important organelles as a subcellular drug-delivery target, since modulation of gene replication and expression is effective for treating various diseases. Here, we demonstrate light-triggered nuclear translocation of guests using caged molecular glue ( Caged Glue-R) tags, whose multiple guanidinium ion (Gu + ) pendants are protected by an anionic photocleavable group (butyrate-substituted nitroveratryloxycarbonyl; BA NVOC). Guests tagged with Caged Glue-R are taken up into living cells via endocytosis and remain in endosomes. However, upon photoirradiation, CagedGlue-R is converted into uncaged molecular glue ( Uncaged Glue-R) carrying multiple Gu + pendants, which facilitates the endosomal escape and subsequent nuclear translocation of the guests. This method is promising for site-selective nucleartargeting drug delivery, since the tagged guests can migrate into the cytoplasm followed by the cell nucleus only when photoirradiated. Caged Glue- R tags can deliver macromolecular guests such as quantum dots (QDs) as well as small-molecule guests. Caged Glue-R tags can be uncaged with not only UV light but also two-photon near-infrared (NIR) light, which can deeply penetrate into tissue.