Membrane Protein and Extracellular Acid Heterogeneity-Driven Amplified DNA Logic Gate Enables Accurate and Sensitive Identification of Cancer Cells

DNA logic gates, as a class of smart molecular devices with excellent biocompatibility and convenient information processing mode, have been widely used for identification of cancer cells based on logic analysis of cancer biomarkers. However, most of the developed DNA logic gates for identification of cancer cells are mainly driven by homogeneous biomarkers such as membrane proteins or RNAs, which may suffer from insufficient accuracy. Herein, we reported a membrane protein and extracellular acid heterogeneity-driven amplified DNA logic gate (HDLG) for accurate and sensitive identification of cancer cells by combining the superior signal amplification characteristics of the hybridization chain reaction (HCR) and the precise computation ability of the logic operation. In this strategy, a DNA aptamer was employed for membrane protein recognition, and a split i-motif was used for the response of the extracellular acid. Only when the two heterogeneous biomarkers existed simultaneously, the DNA logic gate could be driven to perform the "AND" logic operation and induce the formation of an intact trigger to initiate a HCR process on the cell surface, generating an amplified "ON" fluorescence signal. Benefiting from the design of heterogeneity-driven and signal amplification, this DNA logic gate could not only autonomously perform high-resolution fluorescence imaging on the surface of target cancer cells, but also perform sensitive analysis of target cancer cells with a cell number of 70 detected in 200 μL of buffer and desirable accuracy in differentiating target cancer cells from complicated cell mixtures. We anticipate that this novel HDLG is expected to be applied in precise disease diagnosis.