Artificial Nucleic Acid Tractor-Directed Simultaneous Depletion of Oncogenic Membrane Proteins Without Hijacking Proteolysis-Specific Actuator

Targeted protein degradation (TPD) is an emerging tool for degrading proteins of interest, which affords an attractive modality for cancer therapy. However, the present TPD technologies must engage a proteolysis-specific actuator to initiate degradation of targeted proteins in the proteasome or lysosome. Herein, we report an artificial tractor that can induce endocytosis-mediated protein depletion without hijacking a proteolysis-specific actuator. In this de-sign, bispecific aptamer chimeras (BSACs) are estab-lished, which can bridge human epidermal growth factor receptor 2 (ErbB-2), an important biomarker in a common important biomarker in cancer, with membrane proteins of interest. Taking advantage of the property of aptamer-induced endocytosis and digestion of ErbB-2, another membrane protein is translocated into the lysosome in a hitchhike-like manner, resulting in lysosomal proteolysis along with ErbB-2. This strategy frees the TPD from the fundamental limitation of proteolysis-specific actua-tor and allows simultaneous regulation of the quantity and function of two oncogenic receptors in a cell-type-specific manner, expanding the application scope of TPD-based therapeutics.