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

ABSTRACT 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.