Integrated DNA logic platform enables tumor-specific EGFR dimerization inhibition and downstream effector interrogation

DNA-mediated cellular signal regulation strategies have been extensively studied, but most methods treat regulation and assessment as separate processes. Systematically analyzing the real-time correlations between the signaling pathway regulation and downstream effectors remains challenging, which is essential for gaining comprehensive insights into cellular signal transduction. Herein, we proposed a dynamic strategy for selectively triggering dimerization regulation while monitoring downstream effectors to reprogram and annotate cellular signaling. This strategy is facilitated by an AND-gated DNA multiprocessor (TDNYE), which not only triggers dimerization regulation in response to the extracellular tumor microenvironment (TME) and mediates signal regulation to regulate cell behavior, but also in situ monitors the production of downstream effector molecules, thereby providing a means to assess the regulatory effects of the signaling pathways. Given the correlation among TME, epidermal growth factor receptor (EGFR), and matrix metalloproteinase 9 (MMP9) in tumor metastasis, TDNYE employs micro-acidity and ATP as external stimuli, with EGFR serving as the regulatory target and MMP9 serving as the evaluation unit for tumor metastasis-related signals. In the presence of protons and ATP, TDNYE is activated to drive frame nucleic acid and EGFR assembly, thereby regulating the EGFR activity and further inhibiting the production of the pro-metastatic molecule MMP9, which results in cancer cell motility inhibition in the TME. By systematically analyzing these pro-metastasis molecules, the DNA multiprocessor provides insight into their relevance and functions in tumor metastasis. In addition, this logic sensor provides a strategy for precise cellular signaling regulation, offering broad opportunities for in-depth exploration of cellular behavior.