MicroRNAs (miRNAs) are promising biomarkers and therapeutic targets for diverse diseases, particularly cancer; however, intracellular detection coupled with simultaneous therapeutic intervention remains challenging. Here, we describe a self‐assembling DNA probe system that integrates fluorescent miRNA sensing with innate immune activation. This enzyme‐free hybridization chain reaction (HCR) circuit is triggered by oncogenic miR‐21 to generate long nicked double‐stranded DNA (dsDNA) decorated with homodimeric thiazole orange (TO) dyes. In the hairpin state, TO fluorescence is quenched via exciton stacking, and HCR assembly separates the dyes and produces a bright turn‐on signal. Notably, the resulting long nicked dsDNA engages cyclic GMP–AMP synthase (cGAS) and undergoes liquid–liquid phase separation, thereby functioning as a potent agonist of the cGAS–stimulator of interferon gene pathway to activate interferon production and induce selective cytotoxicity in miR‐21‐abundant cancer cells. The system exhibits high sequence selectivity, minimal off‐target effects, and a strong correlation between fluorescence and cytotoxicity. This work establishes a nucleic acid circuit that converts molecular recognition into both a diagnostic signal and a therapeutic response, and provides a modular and biocompatible platform for miRNA‐guided cancer theranostics.
Xu et al. (Mon,) studied this question.