Catalytic DNA Circuit-Driven Surface-Enhanced Raman Scattering Amplification Enables Multiplexed Live-Cell Imaging of Receptor Crosstalk and Feedback Regulation

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The dysregulation of the hepatocyte growth factor/c-mesenchymal-epithelial transition factor (HGF/c-Met) signaling pathway stimulates an invasive epithelial-mesenchymal transition (EMT) and establishes a pathogenic feedback loop by stimulating vascular endothelial growth factor (VEGF) secretion, creating an urgent need for time-resolved, multiplexed imaging technologies. Current receptor dimerization detection methods have limitations in distinguishing oligomeric states and correlating them with downstream activities. Herein, we developed a catalytic DNA circuit-driven surface-enhanced Raman scattering (SERS) amplification (CDCSA) platform for the comprehensive interrogation of the interconnected HGF/c-Met/VEGF network. In this design, the target-triggered catalytic hairpin assembly guided different reporter probes and enhancer probes to form various plasmonic networks, generating amplified, multichannel SERS outputs. This strategy enabled the independent and simultaneous detection of c-Met homodimerization and the corresponding VEGF secretion while also distinguishing between the c-Met/c-Met homodimers and c-Met/VEGFR heterodimers. Additionally, using three mechanistically distinct inhibitors, the CDCSA platform showed excellent functionality in the time-resolved monitoring of drug-receptor interactions in live cells. Overall, by leveraging the inherent programmability of DNA, this method can be widely adapted to diverse cell membrane biomarkers, offering a versatile approach for analyzing complex signaling networks and accelerating targeted drug discovery.