An Endoplasmic Reticulum (ER)‐Targeting DNA Nanodevice for Autophagy‐Dependent Degradation of Proteins in Membrane‐Bound Organelles

Abstract Targeted protein degradation via proteasomal and lysosomal pathways is a promising therapeutic approach, and proteins in cytoplasm or on the cell membrane can be easily contacted and have become the major targets. However, degradation of disease‐related proteins that exist in membrane‐bound organelles (MBO) such as the endoplasmic reticulum (ER) remains unsolved due to the membrane limits. Here we describe a DNA nanodevice that shows ER targeting capacity and undergoes new intracellular degradation via the autophagy‐dependent pathway. Then the DNA nanostructure functionalized with specific ligands is used to selectively catch ER‐localized proteins and then transport them to the lysosome for degradation. Through this technique, the degradation of both exogenous ER‐resident protein (ER‐eGFP) and endogenous overexpressed molecular chaperone (glucose‐regulated protein 78) in cancer cells has been successfully executed with high efficiency.