Multistage‐Responsive Dual‐Enzyme Nanocascades for Synergistic Radiosensitization‐Starvation Cancer Therapy

Abstract Radiotherapy is a common cancer treatment approach in clinical practice, yet its efficacy has been restricted by tumor hypoxia. Nanomaterials‐mediated systemic delivery of glucose oxidase (GOx) and catalase (CAT) or CAT‐like nanoenzymes holds the potential to enhance tumor oxygenation. However, they face the challenge of intermediate (hydrogen peroxide [H 2 O 2 ]) escape during systemic circulation if the enzyme pair is not closely placed to largely decompose H 2 O 2 , leading to oxidative stress on normal tissues. In the present study, a oxygen‐generating nanocascade, n(GOx‐CAT) C7A , constructed by strategically placing an enzymatic cascade (GOx and CAT) within a polymeric coating rich in hexamethyleneimine (C7A) moieties, is reported. During blood circulation, C7A remains predominantly non‐protonated , achieving prolonged blood circulation due to its low‐fouling surface. Once n(GOx‐CAT) C7A reaches the tumor site, the acidic tumor microenvironment (TME) induces protonation of C7A moieties, resulting in a positively charged surface for enhanced tumor transcytosis. Moreover, GOx and CAT are covalently conjugated into close spatial proximity (<10 nm) for effective H 2 O 2 elimination. As demonstrated by the in vivo results, n(GOx‐CAT) C7A achieves effective tumor retention and oxygenation, potent radiosensitization and antitumor effects. Such a dual‐enzyme nanocascade for smart O 2 delivery holds great potential for enhancing the hypoxia‐compromised cancer therapies.