Membrane-Anchored Artificial Receptors for Spatiotemporally Selective Cellular Signaling Modulation

Aberrant phosphorylation of receptor tyrosine kinases (RTKs) is commonly associated with tumorigenesis and metastasis. However, developing specific molecular tools to regulate RTKs phosphorylation and downstream signaling remains challenging. Herein, we develop a programmable and modular membrane-anchored DNA artificial receptor that enables the spatioselective modulation of RTK-related cellular signaling. As a proof of concept, the designed artificial receptor is anchored on a cell membrane with high stability to regulate and monitor the dimerization state of a typical RTK, fibroblast growth factor receptor (FGFR). Real-time observation of the dynamic regulation process is achieved based on single-particle tracking, providing an in-depth perspective of the modulation mechanism from the single-receptor level. Additionally, the artificial receptor system can effectively inhibit the activation of FGFR signaling even in the presence of natural ligands, which reduces protein kinase B and extracellular-regulated kinase 1/2 phosphorylation, further resulting in the cytoskeletal reorganization and upregulation of the pro-apoptotic protein expression. The proposed artificial receptor provides a novel chemical tool to regulate and visualize RTK-associated signaling pathways with tailored stoichiometry and spatial control, providing deep insights into the systematic investigation of receptor-mediated cellular signaling.