Circular Bivalent Aptamer Chimeras Leveraging LDLR-Mediated Lysosomal Shuttling for Targeted Protein Degradation.

Dysregulation of membrane proteins underlies various human diseases, with their overexpression or mutation frequently being associated with cancer progression. Although targeted protein degradation technologies such as proteolysis-targeting chimeras and lysosome-targeting chimeras represent promising therapeutic strategies, their efficacy is often limited by scarce targeting ligands, complex preparation procedures, potential immunogenicity, and other factors. Here, we present a lysosome-targeting degradation platform based on circular bivalent aptamer chimeras (CBACs), which simultaneously engage the lysosomal shuttle receptor LDLR and target membrane proteins. Leveraging the natural LDLR recycling pathway, CBAC triggers receptor-mediated endocytosis and lysosomal degradation while recycling the LDLR. We demonstrate efficient and selective degradation of two cancer-therapeutically relevant membrane proteins, c-Met and PTK7, in multiple cancer cells, leading to apoptosis and reduced invasion and migration. Given its modular design and reliance on endogenous trafficking machinery, this platform holds broad potential for the degradation of diverse membrane proteins and could facilitate the development of new therapeutic modalities.