While proteolysis-targeting chimeras (PROTACs) are showing promise for targeting previously undruggable molecules, their application has been limited by difficulties in identifying suitable ligands and undesired on-target toxicity. Aptamers can virtually recognize any protein through their unique and switchable conformations. Here, by exploiting aptamers as targeting warheads, we developed a novel strategy for inducible degradation of undruggable proteins. As a proof of concept, we chose oncogenic nucleolin (NCL) as the target and generated a series of NCL degraders, and demonstrated that dNCL#T1 induced NCL degradation in a ubiquitin-proteasome-dependent manner, thereby inhibiting NCL-mediated breast cancer cell proliferation. To reduce on-target toxicity, we further developed a light-controllable PROTAC, opto-dNCL#T1, by introducing a photolabile complementary oligonucleotide to hybridize with dNCL#T1. UVA irradiation liberated dNCL#T1 from caged opto-dNCL#T1, leading to dNCL#T1 activation and NCL degradation. These results indicate that aptamer-based PROTACs are a viable alternative approach to degrade proteins of interest in a highly tunable manner.
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