Programmable Morphing DNA Nanodevice Enables Triple Signal Amplification for Long‐Term Early Tumor Metastasis Imaging

Accurate early detection of tumor metastasis remains a formidable clinical challenge owing to the lack of imaging tools that can simultaneously respond sensitively to early metastatic signals and maintain enduring intracellular functionality. Here, we report a programmable morphing DNA nanodevice (PMDN) that integrates catalytic hairpin assembly (CHA) with a hybrid network amplification mechanism to achieve dual-stage intracellular assembly and ultrasensitive detection of metastatic biomarkers. The acidic lysosomal milieu induces i-motif-mediated conformational folding into a compact and nuclease-resistant structure. Following lysosomal escape, cytoplasmic miR-221 triggers a secondary-stage CHA cascade, driving large-scale crosslinking of DNA monomers into a stable nanonetwork. This dynamic bottom-up assembly ensures prolonged intracellular structural integrity of PMDN and concomitantly enables triple-stage signal amplification. Compared with conventional CHA systems, PMDN achieves more than a 200-fold improvement in detection sensitivity, exhibits remarkably persistent fluorescence in MDA-MB-231 cells, and maintains durable tumor localization in vivo for over 10 days. In a metastatic mouse model, PMDN enables early visualization of pulmonary micrometastases through miR-221-activated signal amplification. These results establish environment-adaptive morphing DNA architectures as a powerful platform for real-time monitoring of early metastasis and long-term molecular imaging in complex biological environments.