Caged Molecular Glues as Photoactivatable Tags for Nuclear Translocation of Guests in Living Cells

We developed dendritic caged molecular glues (^CagedGlue-R) as tags for nucleus-targeted drug delivery, whose multiple guanidinium ion (Gu⁺) pendants are protected by an anionic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; ^BANVOC). Negatively charged ^CagedGlue-R hardly binds to anionic biomolecules because of their electrostatic repulsion. However, upon exposure of ^CagedGlue-R to UV light or near-infrared (NIR) light, the ^BANVOC groups of ^CagedGlue-R are rapidly detached to yield an uncaged molecular glue (^UncagedGlue-R) that carries multiple Gu⁺ pendants. Because Gu⁺ forms a salt bridge with PO₄^–, ^UncagedGlue-R tightly adheres to anionic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formation. When tagged with ^CagedGlue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the ^CagedGlue-R tag is photochemically uncaged to form ^UncagedGlue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with ^CagedGlue-R can be delivered efficiently to cell nuclei eventually by irradiation with light