Temperature-Sensitive Nano-GOx Combined with Downregulation of Tumor Stemness to Initiate Robust Antitumor Efficacy

GOx-mediated glucose depletion offers an alternative noninvasive strategy for tumor therapy, but its lower catalytic activity <i>in vivo</i> limits its clinical application. Herein, we designed a temperature-sensitive nano-GOx (NG) that was constructed by gold nanorods chemically modified with GOx (AuNRs-GOx) and coated with temperature-sensitive lipids. The chemical linkage could maintain the natural conformation of GOx, ensuring that NG exerted powerful catalytic activity within the tumor and initiated antitumor immune response through moderate starvation and mild photothermal therapy (mPTT) to coregulating dendritic cells (DCs) and tumor-associated macrophages (TAMs). Ulteriorly, VTNG was obtained by NG coloading with verteporfin (VP) and evofosfamide (TH-302). VTNG demonstrated temperature-sensitive triggered drug release when exposed to near-infrared laser irradiation. NG exacerbated the degree of TME hypoxia and facilitated the activation of TH-302. Meanwhile, VP enhanced tumor cell sensitivity by decreasing the stemness of the tumor cells, thus realizing the effective killing of tumor cells and further enhancing the therapeutic effect of NG. Notably, VTNG had a significant antitumor effect in melanoma models compared with first-line melanoma therapy and formed an immune memory effect. In conclusion, VTNG provided an effective approach to enhance the therapeutic effect of GOx for tumor treatment.