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 Cu_2-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, Cu_2-xO can be vulcanized into Cu_2-xS by overexpressing sulfuretted hydrogen (H₂S) gas in the colorectal tumor for a second near-infrared (NIR-II) light-triggered deep tissue PTT. Cu_2-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.