AbstractMicroRNAs (miRNAs) can act as oncogenes or tumor suppressors, capable of up or down‐regulating gene expression during tumorigenesis; they are diagnostic biomarkers or therapeutic targets for tumors. To detect low abundance of intracellular oncogenic miRNAs (onco‐miRNAs) and realize synergistic gene therapy of onco‐miRNAs and tumor suppressors, a smart nano‐theranostic platform based on dual‐miRNAs guided self‐feedback tetrahedral entropy‐driven DNA circuit is created. The platform as a delivery vehicle is a DNA tetrahedral framework, in which the entropy‐driven DNA circuit achieves a dual‐miRNAs guided self‐feedback, between an in situ amplification of the onco‐miRNAs and activation of suppressor miRNAs release. To test this platform, dual‐miRNAs are selected, miRNA‐155, an up‐regulated miRNA, as cancer indicators, and miRNA‐122, a down‐regulated miRNA as therapy targets in hepatocellular carcinoma, respectively. Through the circuit, the platform to detect onco‐miRNAs at femtomolar level as well as visualized miRNAs inside cells, fixed tissues, and mice is programmed. Furthermore, triggered by miRNA‐155, preloaded miRNA‐122 is amplified via the self‐feedback and released into target cells; the sudden increase of miRNA‐122 and simultaneous decrease of miRNA‐155 synergistically served as therapeutic drugs for gene regulation with enhanced antitumor efficacy and superior biosafety. It is envisioned that this nano‐theranostic platform will initiate an essential step toward tumor theranostics in personalized/precise medicine.