Intracellular Photoactivation of Caspase-3 by Molecular Glues for Spatiotemporal Apoptosis Induction.

Caspase-3 (Casp-3) is an enzyme that efficiently induces apoptosis, a form of programmed cell death. We report a dendritic molecular glue Glue that enables intracellular delivery of Casp-3 and its photoactivation. Glue carrying multiple guanidinium (Gu) ion pendants via photocleavable linkages can tightly adhere to Casp-3 and deliver it into the cytoplasm mainly by direct penetration through the plasma membrane. Casp-3, whose surface is covered by Glue, is unable to interact with its cellular substrates and can therefore not induce apoptosis. However, upon exposure to UV or two-photon near-infrared (NIR) light, Glue is cleaved off to liberate Casp-3, triggering the apoptotic signaling cascade. This intracellular photoactivation of Casp-3 allows spatiotemporal induction of apoptosis in irradiated cells.