Advancements in DNA-Driven Precision Modulation of Cell Surface Receptor for Programmable Cellular Functions

Precise modulation of receptor-mediated signaling is essential for understanding cellular communication and developing targeted therapeutics. Receptor engineering strategies focus on enhancing specificity, manipulating allosteric effects, and controlling receptor clustering. This review comprehensively summarizes recent advances in DNA-based strategies as versatile platforms for receptor engineering, encompassing both genetic and non-genetic approaches. Genetic approaches leverage DNA's protein-coding capability to reprogram receptor function through techniques like domain fusion and site-directed mutagenesis. Complementarily, non-genetic strategies exploit the structural and functional properties of DNA to achieve multidimensional control over receptor functionalities. Specifically, functional nucleic acids (FNAs) confer novel and customizable molecular recognition responsiveness, while DNA nanostructures, such as DNA origami, provide nanoscale spatial precision for regulating receptor valency and oligomerization. Furthermore, programmable dynamic DNA reactions facilitate the development of nanodevices responsive to diverse stimuli, including proteins, small molecules, ions, light, and mechanical forces. Notably, emerging DNA-based logic circuits and nanorobots offer programmable and autonomous control over receptor signaling. Looking forward, integrating genetic and non-genetic DNA engineering strategies holds significant promise at the interface of synthetic biology and DNA nanotechnology, driving the development of next-generation intelligent cellular systems for precise medicine.