An Entropy-Driven Tetrahedral Framework Nucleic Acid Circuit for Assessing Drug Response during Apoptosis through Intracellular MicroRNA Imaging.

Accurate monitoring of apoptosis-related biomarkers is essential for evaluating the drug responses in cancer therapy. Herein, we developed an entropy-driven tetrahedral framework nucleic acid (EDTF) circuit by integrating an entropy-driven DNA strand displacement reaction (EDR) amplifier, an antisense oligonucleotide (ASO)-regulation element, and the chemotherapeutic agent doxorubicin (Dox) into a tetrahedral framework nucleic acid (TFNA) scaffold, enabling the evaluation of drug response during apoptosis through imaging of intracellular microRNA-21 (miR-21). After specific internalization of the EDTF circuit into MCF-7 cells, the EDR amplifier is activated and rapidly amplifies miR-21 via spatially confined DNA strand displacement cascades, leading to the release of fluorophore for in situ imaging. Concurrently, the released ASO and Dox are used for suppression of P-glycoprotein (P-gp) expression and chemotherapy, respectively, thus cooperatively inducing apoptosis and enabling the assessment of drug-induced apoptosis by dynamic imaging of intracellular miR-21. This modular strategy holds considerable potential for extension to the analysis of other nucleic acid biomarkers, as well as for applications in early drug response monitoring, drug screening, and early antitumor therapy.