PDA-Based Nanoplatform with High Ligustilide Loading for Simultaneous Elimination of Breast Cancer Cells and Stem Cells Via BAX/BCL-2/Caspase-3 Pathway Activation

Breast cancer (BC) remains the most prevalent and deadly malignancy among women worldwide. While photothermal therapy (PTT) and chemodynamic therapy (CDT) offer tumor-specific and minimally invasive advantages, their standalone efficacy is limited. Ligustilide (LIG) can exert antitumor effects by generating •O 2–, but its bioavailability is poor, thus necessitating improved delivery strategies. Here, we reported a multifunctional nanoplatform (FeD@LIG) integrating PTT, CDT, and chemotherapy for the simultaneous elimination of breast cancer stem cells (BCSCs) and non-BCSCs. FeD@LIG was synthesized via one-step oxidative polymerization of dopamine, co-loading Fe 3+ and LIG. The nanospheres exhibited excellent photothermal conversion efficiency (52.8%) and pH/GSH-responsive drug release. Upon near-infrared (NIR) irradiation, FeD@LIG triggered ROS generation via Fenton-like reactions and elevated local temperature, leading to enhanced oxidative stress, apoptosis, and LIG release. In vitro, FeD@LIG reduced cell viabilities of MCF-7 and MDA-MB-231 cells to 12.5 and 7.9%, respectively, and significantly inhibited BCSCs’ self-renewal. In vivo, FeD@LIG achieved a tumor inhibition rate of 92.8% with minimal toxicity. Mechanistic studies revealed activation of the BAX/BCL-2/Caspase-3 pathway and suppression of Hedgehog signaling. Overall, FeD@LIG represents a promising nanotherapeutic strategy for overcoming drug resistance and recurrence by inhibiting both BCSCs and non-BCSCs through multimodal synergistic therapy.