A Multi‐Functional Cascade Nanoreactor for Remodeling Tumor Microenvironment to Realize Mitochondria Dysfunction via ROS/Zn²⁺ Ions Overload

Abstract Combining chemo/photodynamic therapy (CDT/PDT) to generate highly harmful reactive oxygen species and cause mitochondria dysfunction is considered a potential strategy to improve the efficiency of anticancer treatment. However, within tumor, the relatively deficient concentration of H₂O₂, hypoxic microenvironment, and overexpressed reduced glutathione (GSH) seriously suppress the efficacy of dynamic therapy. Herein, a multi‐functional cascade nanoreactor, bovine serum albumin modified ZnO₂@CeO₂‐ICG, is reported for remodeling tumor microenvironment (TME) to boost dynamic therapy and realize mitochondria dysfunction via reactive oxygen species (ROS) storm/Zn²⁺ ions overload. Within TME, ZnO₂ decomposed into exogenous H₂O₂ and Zn²⁺ ion. The dual enzyme‐like CeO₂ catalyzes the increased H₂O₂ into ·OH and oxygen molecules respectively, and then the oxygen molecules are translated into ¹O₂ by indocyanine green (ICG) under 808 nm light irradiation to boost PDT. The effective consumption of GSH through the reduction of Ce(IV) ions not only regenerates Ce(III) ions to enhance the efficiency of CDT but also efficaciously alleviates the elimination of ROS generated by dynamic therapy to further improve dynamic therapeutic efficiency. So the improved ROS level under remodeling TME and Zn²⁺ ions acutely lead to mitochondria dysfunction to boost the efficiency of antitumor treatment. Thus, developing functional nanoreactors that enable remodeling TME provides a potential strategy to enhance the efficiency of dynamic therapy.