miRNA-21-triggered DNA nanosystem for aggregation-enhanced photothermal theranostics of breast cancer

Breast cancer treatment is limited by conventional therapies and by the poor photostability and tumor accumulation of photothermal agents such as indocyanine green (ICG). Here, we develop a DNA-based nanosystem, TDN-ICG-Y^py, that undergoes controlled aggregation specifically triggered by the tumor-associated miRNA-21 for targeted fluorescence imaging and enhanced photothermal therapy. The nanosystem integrates a DNA tetrahedron framework, covalently conjugated ICG, and a pyrene-modified Y-shaped structure that serves as both a miRNA-21 sensor and an aggregation inducer. The MUC1 aptamer is incorporated to confer active tumor targeting. Upon miRNA-21 recognition, pyrene excimer fluorescence enables real-time monitoring of aggregation, while ICG aggregation significantly enhances photothermal conversion efficiency and stability. In vitro and in vivo studies demonstrate selective, laser-dependent cytotoxicity, toward cancer cells with minimal effects on normal cells, efficient tumor accumulation, real-time imaging, and effective tumor ablation without observable systemic toxicity. This work establishes a DNA-based theranostic platform that addresses the poor tumor accumulation and photostability of ICG through miRNA-21-triggered aggregation, offering a promising strategy for precise breast cancer treatment.