A Harmless–Harmful Switchable and Uninterrupted Laccase‐Instructed Killer for Activatable Chemodynamic Therapy

Abstract Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular hydrogen peroxide (H₂O₂) into hydroxyl radicals (OH•). Although many studies on H₂O₂ supplementation have been conducted to improve the therapeutic effect of CDT, few studies have focused on the application of superoxide radical (O₂^−•) in CDT, which may result in better efficacy. A major concern about O₂^−•‐mediated CDT is its tendency to induce serious oxidative damage to normal tissues, which may be addressed by using a degradable O₂^−• scavenger. Here, a harmless‐harmful switchable and uninterrupted laccase (LAC)‐instructed killer (HULK) is constructed, which is the first CDT agent accelerated by LAC‐instructed O₂^−• generation and possesses a harmless‐harmful switchable effect because of the photodegradation of the O₂^−• scavenger iron‐chlorin e6 (FeCe6). LAC‐instructed substrate oxidation effectively catalyzes O₂^−• production with the help of intracellular reduction, thereby promoting the conversion of Fe³⁺ to Fe²⁺, accelerating the generation of OH•, and inducing tumor cell apoptosis and necrosis. The introduced O₂^−• scavenger FeCe6 is quickly photodegraded during irradiation, while LAC‐instructed O₂^−• generation proceeds as before, resulting in activatable CDT. This work not only provides the first strategy for LAC‐instructed O₂^−• generation but also presents new insight into activatable CDT.