Abstract

Chemotherapy remains the cornerstone of malignant tumor treatment; however, off‐target effects and severe systemic toxicity limit its efficacy. Here, we developed a programmable theranostic platform based on an all‐in‐one smart DNA nanodevice (SND) that integrates a programmable cancer‐cell classifier (PCC) with a responsive delivery system (RDS). By employing a modular design that permits the customization of aptamer combinations for specific cancer cell types, the platform achieves accurate tumor recognition and spatially controlled drug release. Functioning as a dual‐aptamer molecular guide, the PCC utilizes an interlocked configuration to identify cell‐surface biomarkers in a stepwise manner, thereby ensuring highly specific target cell recognition. The RDS is constructed from a 1D central trunk flanked by double‐stranded drug‐loading units, a structure that confers high payload capacity and nuclease‐enhanced resistance. These peripheral units also function as recognition elements for endogenous stimuli; upon activation, they trigger conformational changes that facilitate efficient intracellular drug release. In vivo studies in tumor‐bearing mice demonstrate that this programmable theranostic platform selectively accumulates in tumor tissues, leading to marked inhibition of tumor growth and a substantial reduction in systemic toxicity. By integrating programmable molecular recognition with stimulus‐responsive drug delivery, our theranostic platform offers a promising strategy for advancing targeted cancer therapy.