Multivalent Aptamer‐Based Lysosome‐Targeting Chimeras (LYTACs) Platform for Mono‐ or Dual‐Targeted Proteins Degradation on Cell Surface

Abstract Selective protein degradation platforms have opened novel avenues in therapeutic development and biological inquiry. Antibody‐based lysosome‐targeting chimeras (LYTACs) have emerged as a promising technology that extends the scope of targeted protein degradation to extracellular targets. Aptamers offer an advantageous alternative owing to their potential for modification and manipulation toward a multivalent state. In this study, a chemically engineered platform of multivalent aptamer‐based LYTACs (AptLYTACs) is established for the targeted degradation of either single or dual protein targets. Leveraging the biotin‐streptavidin system as a molecular scaffold, this investigation reveals that trivalently mono‐targeted AptLYTACs demonstrate optimum efficiency in degrading membrane proteins. The development of this multivalent AptLYTACs platform provides a principle of concept for mono‐/dual‐targets degradation, expanding the possibilities of targeted protein degradation.