Redox-­activatable photothermal therapy and enzyme-mediated tumor starvation for synergistic cancer therapy

Tumor photothermal therapy (PTT) has spatiotemporal controllability, is minimally invasive, has high selectivity for local cancers, and has a good anti-cancer effect; thus, it has been confirmed as a promising cancer treatment. However, regional high temperatures during treatment may damage normal tissues and even induce inflammation and tumor metastasis. In this study, a multifunctional cascade nanoreactor based on hollow mesoporous silica (HMSN) was prepared by loading a photothermal agent (PTA) prodrug of 3,3′,5,5′-tetramethylbenzidine (TMB), glucose oxidase (Gox), and horseradish peroxidase (HRP), which are used for the synergistic cancer therapy of starvation therapy (ST) and PTT. First, the adenosine triphosphate(ATP) generation of tumor cells was obstructed using Gox-mediated starvation therapy, and the heat shock protein-70 (HSP-70) level was further used to reduce the thermo-resistance. Then, HRP improved the hypoxic state of the tumor microenvironment (TME) by consuming H2O2 and further oxidizing the colorless TMB(PTA prodrug) into OXTMB (PTA) with an excellent photothermal effect. In addition,the glutathione(GSH) level of the tumor cells was also downregulated, which further promoted the process of apoptosis. Ultimately, both the in-vivo and in-vitro studies showed that the nanoreactor significantly inhibited the growth of tumor cells and ablated the solid tumor, which provides another possibility for clinical intervention.