Bioorthogonally Activatable Autophagy-Tethering Compounds for Aptamer-Guided Mitochondrial Degradation

Although macroautophagy degradation targeting chimeras (MADTACs) have been demonstrated to be efficient in a broad spectrum from intracellular proteins to macromolecular complexes such as lipid droplets and the mitochondrion, MADTACs still face degradation of uncontrolled protein in normal cells and cause systemic toxicity, thus limiting their therapeutic applications. Herein, we employ bioorthogonal chemistry to develop a spatially controlled MADTACs strategy. Separated warheads display no activity in normal cells but can be activated by aptamer-based Cu nanocatalyst (Apt-Cu³⁰) in tumors specifically. These in situ synthesized chimera molecules (bio-ATTECs) can degrade the mitochondrion in live tumor cells and subsequently induce autophagic cell death, which has been further demonstrated by lung metastasis melanoma murine models. To the best of our knowledge, this is the first bioorthogonal activated MADTAC in live cells for inducing autophagic tumor cell death, which may promote the development of cell-specific MADTACs for precision therapeutics by avoiding undesired side effects.