DNA-based nanostructures for cell membrane receptor regulation and disease treatment

The aberrant expression and dysfunction of cell membrane receptors are closely associated with the onset and progression of various major diseases, such as cancer, neurodegenerative disorders, and inflammation. However, conventional membrane protein regulation strategies, such as small-molecule inhibitors or antibody-based therapies, face several challenges, including target dependency, limited degradation scope, and the development of drug resistance. In recent years, DNA nanostructure has emerged as an innovative solution for the precise modulation of membrane receptors, owing to its high programmability, precise spatial control, and dynamic responsiveness. This review provides a comprehensive overview of the design strategies and recent progress in the application of DNA nanostructures for membrane protein regulation, with a particular emphasis on their pivotal roles in spatial blockade, spatial reorganization, and targeted degradation of membrane receptors. By rationally designing DNA origami, aptamer-based nanoarrays, and dynamic responsive devices, researchers have achieved precise control over receptor dimerization, oligomerization, and membrane compartmentalization, thereby modulating downstream signaling pathways. In addition, DNA nano-degradation platforms based on proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras (LYTACs), and the autophagy-lysosome pathway have significantly enhanced the efficiency of membrane protein degradation while demonstrating excellent tumor selectivity. DNA nanostructures have been successfully applied in cancer immunotherapy, interventions for neurodegenerative diseases, and the regulation of metabolic disorders, offering new strategies for targeting previously “undruggable” proteins. This review highlights recent breakthroughs in the field and outlines future directions and clinical translation potential of DNA nanostructures for membrane protein regulation.