Double metal nanoparticles loaded and NIR/pH dual responsive drug nanocrystals inhibit cancer stem cells in a multi-modal manner

•CSCs resist conventional chemotherapy via multi-factor regulated mechanisms.•A combined tumor therapy strategy forms a multi-dimensional control network.•Double metal nanoparticles based nanoconjugates defeat CSCs via multiple targets.•Molecular mechanism refers to REDOX imbalance, downregulated CSCs and EMT markers.•This sandwich nanostructure provides a new combinatorial strategy in cancer treatment. The defeat of cancer is still a challenge due to the existence of cancer stem cells (CSCs), since they resist conventional chemotherapy via multi-factor regulated mechanisms. Consequently, one-dimensional action towards CSCs cannot work. Herein, we used rationally designed hybrid nanoparticles as a combined cancer therapy, hoping to form a multi-dimensional control network. In this paper, double metal nanoparticles (AuNPs and AgNPs) decorated Camptothecin nanocrystals using hyaluronic acid as a connection bridge were formulated according to complementary anti-CSCs activities from gold, silver, organic drug and CSCs targeted hyaluronic acid. This sandwich nanostructure demonstrated effective cytotoxic/apoptotic/necrotic activity against bulk MDA-MB-231 cells and their CSCs subpopulation, and suppressed spheroids formation and phenotypes of CSCs, in particular under laser ablation. This activity was ascribed to their NIR-pH dual responsive drug release, multiple targeting properties, synergistic thermo-chemotherapy of organic drug and inorganic metal nanoparticles, enhanced cellular uptake, and versatile acting sites and toxicity profiles from each component. Anti-CSCs activity of this novel drug formulation was in a multi-modal manner, such as impact on quiescence state of CSCs, a reduction in their stemness and self-renewable capacity and recovery of their chemo-sensitivity. The molecular mechanism was due to changes in redox balance inside CSCs, a lower level in CSCs markers including Sox-2, Nanog, CD44 and ALDH1 and downregulation in drug efflux pump (Pgp) and EMT related factors (Slug and Snail). This thermo-chemotherapy platform provides a new combinatorial strategy in complete elimination of CSCs. [Display omitted]