RNA-Seq-guided triple-combination nano-system of gold nanocluster, quercetin, and docetaxel for ultimate synergistic photothermal-chemotherapy against MDR tumor

For oncological purposes, hyperthermia has increasingly emerged as a good therapeutic option for patients without fitness to undergo surgery, or for those with surgically inaccessible tumors. However, tumor recurrence after photothermal therapy constitutes a significant barrier to achieving good survival outcome. In this study, we used a gold nanocluster (GNC) micelle system capable of multiple NIR laser exposure; RNA-seq analysis revealed that repeated NIR exposure upregulates heat-shock protein and cell-cycle process-related genes that could be associated with tumor recurrence. To prevent recurrence, we presented an RNA-seq-guided drug combination strategy of GNC, docetaxel, and quercetin via a nano-system. Quercetin treatment downregulated heat-shock protein expression and inhibited function of P-gp with mild antitumor activity. Furthermore, docetaxel treatment demonstrated antitumor activity with significant G2-M cell-cycle arrest. When two of GNC, docetaxel, and quercetin were administered together, they showed a synergistic antitumor effect, whereas when the drugs were administered simultaneously in a triple combination, a very strong synergistic effect was achieved, as indicated through increased apoptosis induction and cell-cycle arrest in vitro and in vivo. The data from this study emphasize the benefit of triple combination and outlines potential translational directions for photothermal-chemotherapy.