Tumor-microenvironment-mediated second near-infrared light activation multifunctional cascade nanoenzyme for self-replenishing O2/H2O2 multimodal tumor therapy.

Developing a catalytic nanoenzyme activated by the tumor microenvironment (TME) shows excellent potential for in situ cancer treatment. However, the rational design of a cascade procedure to achieve high therapeutic efficiency remains challenging. In this study, the colorectal TME-responsive multifunctional cascade nanoenzyme Cu2-xO@MnO2@glucose oxidase (GOx)@hyaluronic acid (HA) was developed to target in situ cancer starvation/chemodynamic therapy (CDT)/photothermal therapy (PTT). First, the MnO2 nanolayer specifically decomposes within the acidic TME to generate Mn2+ and oxygen (O2), thereby alleviating the hypoxic TME. Subsequently, Cu2-xO can be vulcanized into Cu2-xS by overexpressing sulfuretted hydrogen (H2S) gas in the colorectal tumor for a second near-infrared (NIR-II) light-triggered deep tissue PTT. Cu2-xS nanoparticles can react with hydrogen peroxide (H2O2) to generate hydroxyl radical (OH) for the CDT. In addition, GOx catalyzes the conversion of glucose into H2O2 for starvation therapy and enhances the CDT efficiency by self-supplying H2O2. Interestingly, the generated reactive oxygen species (ROS) induce immunogenic cell death (ICD), which further activates adaptive cancer immunity for anti-tumor immunotherapy. Finally, therapeutic efficiency was greatly improved after coating with tumor-targeted HA. Collectively, these TME-responsive cascade nanoenzymes can realize PTT, CDT starvation therapy, and immunotherapy, paving the way for the design of TME-responsive cascade nanoenzymes for synergistically enhanced tumor-specific therapy.