A GSH/APE1-Controlled Framework Nucleic Acids based Entropy-Driven DNA Circuit for High-Contrast miRNAs Imaging

Catalytic DNA circuits show great potential for precise intracellular imaging. However, their selectivity and efficiency are often hindered by low anti-interference performance in the cytoplasm's complex environment. Thus, designing DNA circuits that exhibit enhanced stability and specific activation is crucial for the accurate intracellular biomolecule imaging. Herein, we proposed a framework nucleic acids based endogenously activated entropy-driven catalytic (EDC) circuit, FEED, for in vivo microRNA imaging with enhanced selectivity and efficiency. To mitigate undesired signal leakage before reaching the target cells, the dominating EDC circuitry fuel strand was initially blocked with a disulfide bond modified DNA strand, and the target recognition site of sensing module was also closed by apurinic/apyrimidinic (AP) sites. This configuration allowed selective activation of the EDC by endogenous GSH and human apurinic/apyrimidinic endonuclease 1 (APE1) in cancer cells, facilitating high-contrast miRNA imaging. Additionally, the integrating a distinctive DNA tetrahedral structure into the EDC circuit enhances both biostability and cellular reaction efficacy. This in-site activation FEED circuit offers a programmable and modular amplification strategy for biomarker detection in live cells and mice, providing a potentially valuable molecular tool for living systems.