Tumor-microenvironment-mediated second near-infrared light activation multifunctional cascade nanoenzyme for self-replenishing O/HO 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 CuO@MnO@glucose oxidase (GOx)@hyaluronic acid (HA) was developed to target in situ cancer starvation/chemodynamic therapy (CDT)/photothermal therapy (PTT). First, the MnO nanolayer specifically decomposes within the acidic TME to generate Mn and oxygen (O), thereby alleviating the hypoxic TME. Subsequently, CuO can be vulcanized into CuS by overexpressing sulfuretted hydrogen (HS) gas in the colorectal tumor for a second near-infrared (NIR-II) light-triggered deep tissue PTT. CuS nanoparticles can react with hydrogen peroxide (HO) to generate hydroxyl radical (OH) for the CDT. In addition, GOx catalyzes the conversion of glucose into HO for starvation therapy and enhances the CDT efficiency by self-supplying HO. 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.