A Versatile Multidrug Coloaded Nanoplatform Integrating Photothermal-Differentiation-Chemotherapy for Breast Cancer Stemness Inhibition

Cancer stem cells (CSCs) are a subpopulation of tumor cells with strong tumorigenic ability and high resistance to conventional therapeutic strategies due to the protected niche and poor drug penetration. While self-assembled nanosystems based on small-molecule self-assembly show therapeutic promise, limitations such as low targeting and unstable drug release still constrain their applications. In this study, we developed CD44-targeted RHID (ICG-DOX@RA-HA-DOX) nanocomplexes with a shell of hyaluronic acid-retinoic acid-doxorubicin (RA-HA-DOX) conjugates and a core of DOX-indocyanine green (ICG), which exhibited sustained and pH-responsive release properties. The released DOX and ICG could synergistically eliminate bulk tumors via chemotherapy and photothermal therapy. Concurrently, the released RA could promote CSC differentiation, further reducing stemness, self-renewal, and mammosphere formation, thereby enhancing the therapeutic sensitivity of CSCs to combined therapy. This integrated photothermal-differentiation-chemotherapy approach demonstrated strong antitumor efficacy both in vitro and in vivo, providing a promising nanotherapeutic strategy against CSC-driven malignancies.