Spatiotemporally Controlled Nuclear Translocation of Guests in Living Cells Using Caged Molecular Glues as Photoactivatable Tags

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 (^CagedGlue-R) tags, whose multiple guanidinium ion (Gu⁺) pendants are protected by an anionic photocleavable group (butyrate-substituted nitroveratryloxycarbonyl; ^BANVOC). Guests tagged with ^CagedGlue-R are taken up into living cells via endocytosis and remain in endosomes. However, upon photoirradiation, ^CagedGlue-R is converted into uncaged molecular glue (^UncagedGlue-R) carrying multiple Gu⁺ pendants, which facilitates the endosomal escape and subsequent nuclear translocation of the guests. This method is promising for site-selective nuclear-targeting drug delivery, since the tagged guests can migrate into the cytoplasm followed by the cell nucleus only when photoirradiated. ^CagedGlue-R tags can deliver macromolecular guests such as quantum dots (QDs) as well as small-molecule guests. ^CagedGlue-R tags can be uncaged with not only UV light but also two-photon near-infrared (NIR) light, which can deeply penetrate into tissue.