A Cascade Nanoreactor of Metal‐Protein‐Polyphenol Capsule for Oxygen‐Mediated Synergistic Tumor Starvation and Chemodynamic Therapy

Abstract Starvation therapy kills tumor cells via consuming glucose to cut off their energy supply. However, since glucose oxidase (GOx)‐mediated glycolysis is oxygen‐dependent, the cascade reaction based on GOx faces the challenge of a hypoxic tumor microenvironment. By decomposition of glycolysis production of H 2 O 2 into O 2 , starvation therapy can be enhanced, but chemodynamic therapy is limited. Here, a close‐loop strategy for on demand H 2 O 2 and O 2 delivery, release, and recycling is proposed. The nanoreactor (metal‐protein‐polyphenol capsule) is designed by incorporating two native proteins, GOx and hemoglobin (Hb), in polyphenol networks with zeolitic imidazolate framework as sacrificial templates. Glycolysis occurs in the presence of GOx with O 2 consumption and the produced H 2 O 2 reacts with Hb to produce highly cytotoxic hydroxyl radicals (•OH) and methemoglobin (MHb) (Fenton reaction). Benefiting from the different oxygen carrying capacities of Hb and MHb, oxygen on Hb is rapidly released to supplement its consumption during glycolysis. Glycolysis and Fenton reactions are mutually reinforced by oxygen supply, consuming more glucose and producing more hydroxyl radicals and ultimately enhancing both starvation therapy and chemodynamic therapy. This cascade nanoreactor exhibits high efficiency for tumor suppression and provides an effective strategy for oxygen‐mediated synergistic starvation therapy and chemodynamic therapy.