Reduced graphene oxide quantum dots/manganese dioxide/glucose oxidase nanoparticles for cascade catalytic cancer treatment in multimodal starvation therapy-augmented chemodynamic/photothermal therapy

Combination cancer therapy can boost the overall treatment efficacy using functional nanomaterials that specifically target cancer cells. Furthermore, the treatment outcome can be improved by focusing on specific characteristics in the tumor microenvironment (TME). In this study, tumor-targeting multifunctional nanoparticles were constructed from reduced graphene oxide quantum dots (rGOQD), manganese dioxide (MnO₂), glucose oxidase (GOx), and cell-penetrating peptide (CPP). The rGOQD/MnO₂/GOx/CPP nanoparticles can treat tumors by strengthening chemodynamic/photothermal therapy (CDT/PTT) with starvation therapy (ST). The MnO₂ reacts with high concentrations of endogenous H₂O₂ in an acidic TME to produce reactive oxygen species (ROSs) from Mn²⁺. The highly cytotoxic hydroxyl radical (•OH) kills cancer cells and initiates CDT. The MnO₂ can also consume the •OH scavenger glutathione (GSH) in cancer cells and eliminate their antioxidant defense. The GOx oxidizes glucose to cause cancer cell glucose starvation for ST, which produces H₂O₂ to boost the efficacy of CDT. By consuming glucose, ST mediated by GOx leads to reduced ATP production in the glycolysis pathway. This downregulates the expression of ATP-dependent heat shock proteins that provide cancer cell thermal resistance when the photothermal agent rGOQD is irradiated with near-infrared (NIR) light for PTT. Therefore, we prepare different rGOQD-based nanoparticles and characterize their physicochemical and biological properties. The nanoparticles were studied in vitro against U87 glioblastoma cells for targeted cancer therapy. Using nude mice bearing subcutaneous U87 tumors, the in vivo study indicates rGOQD/MnO₂/GOx/CPP plus NIR irradiation can substantially inhibit the tumor growth rate without causing adverse effects from CPP-mediated trimodal ST/CDT/PTT.