44 Bi-specific antibodies targeting C1q and a tumor antigen activate the complement system independent of C1q-Fc interactions

The ability to regulate protein abundance provides huge opportunities for the development of treatments for various diseases. The proteolysis-targeting chimera (PROTAC) provides powerful tools to degrade these undruggable targets, becoming a promising technology. Herein, we report the development of aptamer-based PROTACs as a novel strategy to broaden the spectrum of targets. The RNA aptamer of the target protein applied in targeted degradation. A heterobifunctional molecule can recruit E3 ubiquitin ligase to a genetically encoded tandem aptamer RNA scaffold, promoting ubiquitination and degradation of target proteins. Partial degradations of different target proteins, including p50, p65, and E2F1, have been achieved by simply replacing the 3′ module on the RNA scaffold with the corresponding RNA aptamers. Besides, simultaneous degradation of multiple target proteins is realized through inserting more aptamer into RNA scaffold. Thus, the aptamer-based PROTAC technology offers a general strategy for targeted protein degradation in drug discovery and biological research.