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

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