A multi-modal imaging hyaluronic acid micelle for enhanced mild photothermal therapy of triple-negative breast cancer

Mild photothermal therapy (PTT) for cancer treatment has gained significant attention due to its selective targeting of cancer cells and the mildness of the treatment. However, its efficacy is limited by tumor heterogeneity and the resistance of cancer cells to treatment. The self-renewal capacity of therapy-resistant cancer stem cells (CSCs) and the activation of epithelial-mesenchymal transition (EMT) in cancer cells largely contribute to the recurrence and metastasis of residual tumors. In this study, we developed a self-assembling micelle (HA-ADH@IR808) with CD44-targeting capabilities, designed to enhance the performance of mild PTT in the treatment of triple-negative breast cancer (TNBC). The hydrazide group within the HA-ADH@IR808 micelles generates a strong chemical exchange saturation transfer (CEST) signal at 4.4 ppm and 5.4 ppm, enabling precise intratumoral mapping of the photosensitizer. Multi-modal imaging enhances the efficacy of mild PTT by enabling accurate localization of the photosensitizer and real-time monitoring of treatment temperature, thereby minimizing side effects. In vivo experiments revealed that CD44-targeted mild PTT significantly inhibits cancer cell proliferation, suggesting that the selective ablation of CD44⁺ cells—predominantly CSCs—results in reduced tumor growth and metastatic potential. In addition, our study found that low-temperature photothermal treatment induced the degradation of collagen I in the tumor extracellular matrix (ECM), which subsequently led to a reduction in the expression of proteins associated with the EMT pathway. Overall, this study provides new insights into the design of mild photothermal therapeutic micelles, as well as advancements in in vivo visualization and treatment monitoring.