Proximity-Induced Phosphatase-Recruiting DNA Feedback Switch for Self-Adaptive Modulation of Receptor Signaling and Cell Behavior

Transmembrane receptors orchestrate cell fate decisions and maintain tissue homeostasis through exquisitely regulated signaling cascades, whereas their dysregulation drives disease initiation and progression. Although a variety of stimulus-responsive strategies have been developed to manipulate receptor activity, regulation of cellular processes in response to spatially defined cues, such as molecular proximity, remains a major challenge. Herein, we developed a proximity-induced phosphatase-recruiting DNA feedback switch (PPDFS) that emulates natural receptor feedback regulation to achieve specific and self-adaptive modulation of receptor signaling. Leveraging the programmability of DNA nanostructures and aptamer-mediated molecular recognition, the proximity sensors of PPDFS sensitively detect receptor dimerization at the cell surface and activate an actuator module to recruit the phosphatase PTPRF. Receptor proximity thus not only initiates signaling activation but also simultaneously triggers the inhibitory response of PPDFS, thereby maintaining signaling homeostasis and restraining malignant cellular behaviors. Furthermore, PPDFS-mediated regulation of cellular responses elucidates the complete cascade linking receptor signaling to epithelial-mesenchymal transition (EMT), cytoskeletal reorganization, and cell movement. With its modular design, PPDFS can be readily adapted to diverse receptor systems for precise control of transmembrane signaling. Our work presents a bioinspired nanomedicine platform that bridges receptor signaling, DNA nanotechnology, and adaptive therapy.