Iridium/ruthenium nanozyme reactors with cascade catalytic ability for synergistic oxidation therapy and starvation therapy in the treatment of breast cancer.

Abstract

The application of nanozymes to specifically treat tumors in the tumor microenvironment (TME) would be a novel and effective strategy. Here, ultra-small IrRu alloy nanoparticles (IrRu NPs) with dual enzyme activities were synthesized by a simple method. PEG surface modification was carried out to improve the biocompatibility of nanoparticles. Meanwhile, the natural enzyme glucose oxidase (GOx) was loaded to synthesize a multi-enzyme nanoreactor (IrRu-GOx@PEG NPs) that could undergo cascade catalytic reaction. In the first catalytic stage, GOx in IrRu-GOx@PEG NPs degraded tumor tissue-sensitive glucose to hydrogen peroxide (H₂O₂), which cut off the nutrient source of the tumor and inhibited tumor growth by starvation therapy. In the second catalytic stage, IrRu NPs in IrRu-GOx@PEG NPs catalyzed the upstream endogenous H₂O₂ to highly toxic singlet oxygen ¹O₂ and O₂. Among them, ¹O₂ could directly induce apoptosis of cancer cells by the oxidative therapy, and O₂ could resolve the problem of hypoxia that easily led to the termination of the starvation therapy response in tumor microenvironment, thereby making the cycle of starvation therapy-related reactions continue to occur. It also inhibited the metastasis of tumors caused by hypoxia. In vitro catalytic activity studies showed that IrRu-GOx@PEG NPs had good and stable catalytic activity and could effectively induce apoptosis of 4T1 cancer cells. In addition, in vivo results further demonstrated that IrRu-GOx@PEG NPs could effectively treat breast cancer in combination with starvation therapy and oxidative therapy. This treatment strategy is expected to be used in the treatment of other cancers, bringing new treatment strategies for cancer treatment.