Cooperatively designed aptamer-PROTACs for spatioselective degradation of nucleocytoplasmic shuttling protein for enhanced combinational therapy
Ran Liu, Zheng Liu, Mohan Chen, Hang Xing, Penghui Zhang, Jingjing Zhang
Abstract
Nucleocytoplasmic shuttling proteins (NSPs) have emerged as a promising class of therapeutic targets for many diseases. However, most NSPs-based therapies largely rely on small-molecule inhibitors with limited efficacy and off-target effects. Inspired by proteolysis targeting chimera (PROTAC) technology, we report a new archetype of PROTAC (PS-ApTCs) by introducing a phosphorothioate-modified aptamer to a CRBN ligand, realizing tumor-targeting and spatioselective degradation of NSPs with improved efficacy. Using nucleolin as a model, we demonstrate that PS-ApTCs is capable of effectively degrading nucleolin in the target cell membrane and cytoplasm but not in the nucleus, through the disruption of nucleocytoplasmic shuttling. Moreover, PS-ApTCs exhibits superior antiproliferation, pro-apoptotic, and cell cycle arrest potencies. Importantly, we demonstrate that a combination of PS-ApTCs-mediated nucleolin degradation with aptamer-drug conjugate-based chemotherapy enables a synergistic effect on tumor inhibition. Collectively, PS-ApTCs could expand the PROTAC toolbox to more targets in subcellular localization and accelerate the discovery of new combinational therapeutic approaches.