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 ERresident protein (ER-eGFP) and endogenous overexpressed molecular chaperone (glucose-regulated protein 78) in cancer cells has been successfully executed with high efficiency.

Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation

“…With the deepening exploration of the endocytic-lysosomal and autophagic-lysosomal degradation pathways, targeting protein degradation (TPD) strategies through the lysosomal pathway have arisen in recent years. These encompass protein degradation through the endocytic-lysosomal pathway such as lysosome-targeting chimaeras (LYTAC), 3−5 antibody-based PROTAC (AbTAC), 6 bispecific adapter chimeras, 7,8 and covalent nanobody-based PROTAC strategy (GlueTAC), 9 as well as technologies for degrading target molecules through the autophagic-lysosomal pathway such as autophagy-tethering compounds (ATTEC), 10 autophagy-targeting chimera (AUTAC 11,12 and AUTOTAC), 13 ER-targeting DNA nanodevice for autophagy-dependent degradation, 14 and autophagytargeting nanobody chimera (ATNC). 15 The composition of commonly targeted proteins or lysosomes includes antibodies, [3][4][5]9,15 nucleic acid aptamers, 7,8 peptides, 9 and small molecules.…”

Molecular Design Strategy of Protein Isoform-Specific Fluorescent Probes by Considering Molecule in Its Entirety

“…Protein recognition, particularly protein isoform-specific recognition, is of great significance for accurate clinical diagnosis and academic research. Among many biological analysis methods, organic fluorescent probes are widely used to recognize proteins in living simples due to their high selectivity, remarkable sensitivity, excellent spatial resolution, noninvasiveness, and fast and easy operation. − …”