A multimodal combination therapy for suppressing cancer stem cell and cancer cells

The presence of cancer stem cell (CSC) leads to the failure in triple-negative breast cancer treatment because conventional therapy is hard to prevent CSC proliferation. A multimodal combination therapy strategy by ferroptosis, pyroptosis, and differentiation is proposed to address it. This nano-platform is consisted with metal-phenolic network nanoparticles loading with drug β-Lapachone (MPN@Lap) and nanoparticles encapsulating drug all-trans retinoic acid ( ABS ATRA). On one hand, MPN@Lap nanoparticles effectively enhanced cancer cellular reactive oxygen species (ROS) level by the double circulation of β-Lapachone reduction and Fenton reaction, thereby depleting glutathione for the accumulation of lipid peroxidation and cleaving cysteinyl aspartate-specific proteases 3 for gasdermin E dissociation, further causing the dual activation of ferroptosis and pyroptosis concurrently. On the other hand, all-trans retinoic acid released from ABS ATRA nanoparticles reduced the proportion of stemness-related cell population of CD44 + /CD24 − and the expression of stem cell marker aldehyde dehydrogenase 1 for stemness inhibition. With a high ROS level and the damage of mitochondrial membrane potential, redox homeostasis in CSC is destructed and it further facilitated and amplified the differentiation process. Studies demonstrated that this dual-action approach synergistically inhibited tumor growth and eradicated CSC stemness by ferroptosis, pyroptosis, and differentiation. Therefore, this study provides a novel cancer cells and CSC dual-acting strategy with multimodal combination approaches of ferroptosis, pyroptosis, and differentiation to combat breast cancer cells, which also offers advice for treating CSC-driven malignancies.