Combining Cobalt Ferrite Nanozymes with a Natural Enzyme to Reshape the Tumor Microenvironment for Boosted Cascade Enzyme-Like Activities.

Nanozymes with the merits of effective enzyme-mimic activities, tunable catalytic properties, pH/temperature tolerance, and high stability have been consumingly researched for nanocatalytic therapy. Herein, the union nanozymes and a natural enzyme nanoplatform (DMSN@CoFe 2 O 4 /GOD-PCM) are elaborately designed by simply depositing an ultrasmall cobalt ferrite (CoFe 2 O 4 ) bimetallic oxide nanozyme and natural glucose oxidase (GOD) that are loaded into the aperture (∼12 nm) of dendritic mesoporous silica (DMSN) for near-infrared-II-enhanced tumor therapy. Upon irradiation, the hyperthermia generated by CoFe 2 O 4 nanozymes unlocks the "gate" of phase-change material (PCM) for releasing GOD, which reshapes the specific tumor microenvironment (TME) through the glucose metabolism pathway. The resulting strengthened acid condition and a considerable amount of H 2 O 2 efficiently initiate the cascade catalysis reactions. Moreover, highly toxic hydroxyl radicals are generated with a Co/Fe dual-cycle system of ultrasmall CoFe 2 O 4 nanozymes. The in situ glutathione consumption and hypoxia relief further amplify oxidative stress. In addition, chemotherapeutic effects due to the cytotoxicity of cobalt ions enhance the therapeutic performance. Collectively, this study provides a proof of concept for TME-reshaped natural and artificial nanozyme cascade catalysis for combined reactive oxygen species-based therapy and chemotherapy.