A Multi‐Pathway Integrated DNA Logic Circuit for Precise Cancer Identification

Accurate and sensitive identification of cancer cells is of great importance for cancer diagnosis and prognosis. DNA circuits with high sensitivity have promise for detecting tumor-associated molecules, yet are constrained with limited tumor specificity due to the "on target, off cancer" effect. To address this issue, we propose a multi-pathway integrated DNA logic circuit (MDLC) system by integrating two AND-gate circuit modules for the highly specific and sensitive identification of cancer cells. Upon delivery into cancer cells, the MDLC system is synergistically activated by the three distinct tumor-specific biomarkers (O6-methylguanine-DNA methyltransferase, Apurinic/apyrimidinic endonuclease 1, and microRNA-21), thereby triggering a cascaded DNA circuit to generate amplified fluorescence signals. The MDLC system promises high specificity and broad applicability, which enables effective identification of three positive cancer cells (MCF-7, HepG2, and MDA-MB-231) from normal cells (MCF-10A). Further in vivo studies demonstrate the ability of this system to precisely recognize cancer cells and therefore excels in tumor imaging. Collectively, this work illustrates a simple and powerful strategy for developing DNA logic circuits, bringing new avenues for precise cancer diagnosis and biomedical applications.