A Cascade Nanozyme with Amplified Sonodynamic Therapeutic Effects through Comodulation of Hypoxia and Immunosuppression against Cancer

The tumor microenvironment (TME) featured by immunosuppression and hypoxia is pivotal to cancer deterioration and metastasis. Thus, regulating the TME to improve cancer cell ablation efficiency has received extensive interest in oncotherapy. However, to reverse the immunosuppression and alleviate hypoxia simultaneously in the TME are major challenges for effective cancer therapy. Herein, a multifunctional platform based on Au nanoparticles and a carbon dots modified hollow black TiO2 nanosphere (HABT-C) with intrinsic cascade enzyme mimetic activities is prepared for reversing immunosuppression and alleviating hypoxia in the TME. The HABT-C NPs possess triple-enzyme mimetic activity to act as self-cascade nanozymes, which produce sufficient oxygen to alleviate hypoxia and generate abundant ROS. The theoretical analysis demonstrates that black TiO2 facilitates absorption of H2O and O2, separation of electron–holes, and generation of ROS, consequently amplifying the sonodynamic therapy (SDT) efficiency. Specifically, HABT-C exhibits favorable inhibition of immunosuppressive mediator expression, along with infiltrating of immune effector cells into the TME and reversing the immunosuppression in the TME. As a result, HABT-C can effectively kill tumor cells via eliciting immune infiltration, alleviating hypoxia, and improving SDT efficiency. This cascade nanozyme-based platform (HABT-C@HA) will provide a strategy for highly efficient SDT against cancer by modulation of hypoxia and immunosuppression in the TME.