A DNA Logic-Gated Cascade Amplification Biosensor for Highly Specific Electrochemical Detection of Circulating Tumor Cells

Circulating tumor cells (CTCs) are rare cancer-derived cells in peripheral blood, carrying vital information about tumor heterogeneity and progression. Their reliable detection remains challenging due to extreme rarity and high background interference. Herein, we report an electrochemical biosensor that integrates a DNA-based AND logic gate with cascaded signal amplification for the specific and sensitive determination of CTCs. The system requires the co-recognition of EpCAM and MUC1 on the cell surface via corresponding aptamers, which initiates an amplification cascade comprising hybridization chain reaction, DNAzyme-mediated cleavage, and entropy-driven assembly. This cascade ultimately results in the in situ formation of a DNA network on the electrode, enabling the capture of platinum-coated gold nanoparticles (Au@PtNPs) via biotin–streptavidin interaction, thereby significantly enhancing the electrocatalytic signal. The biosensor exhibits a linear response from 50 to 2.5 × 105 cells mL–1 with a detection limit down to 14 cells mL–1. It also exhibits high selectivity against nontarget cells, isolated proteins, and cellular debris, and displays excellent stability in serum and whole blood. Thus, this work may provide a reliable and clinically translatable strategy for CTC-based liquid biopsy, highlighting its potential for personalized lung cancer management.