Abstract

RNA-ATTEC enables programmable autophagy-based protein degradation. • Bypasses UPS limits, degrades diverse targets via autophagy-lysosome pathway. • Modular aptamer scaffold degrades transcription factors, RBPs, and EGFR. • No small-molecule pockets needed; targets “undruggable” proteins lacking ligands. Targeted protein degradation (TPD) has emerged as a breakthrough in drug discovery and a global biomedical research hotspot. However, its reliance on traditional small-molecule ligands inherently restricts the scope of targetable proteins. Herein, we report a novel autophagosome-tethering compound (ATTEC) strategy based on RNA aptamers to expand the target applicability of this technology. We designed and constructed a heterobifunctional molecule (GWD) that specifically recruits the autophagy protein LC3 to a genetically encoded tandem aptamer RNA scaffold. This scaffold recognizes target proteins via RNA aptamers, delivering them into the autophagy-lysosome degradation pathway. Through modular replacement of aptamer units on the RNA scaffold, we achieved efficient degradation of multiple transcription factors (E2F1, p50, p65). Furthermore, using this strategy, we demonstrated targeted degradation of the RNA-binding protein RBFOX1 and the oncoprotein EGFR in cervical cancer cells (HeLa). Collectively, this aptamer-based ATTEC platform provides a modular, programmable, and versatile strategy for targeted protein degradation, holding great promise for innovative drug discovery and fundamental biological research. Download: Download high-res image (73KB) Download: Download full-size image