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

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular hydrogen peroxide (H₂ O₂ ) into hydroxyl radicals (OH•). Although many studies on H₂ O₂ 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.