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 (H2O2) into hydroxyl radicals (OH center dot). 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 (O-2(-center dot)) in CDT, which may result in better efficacy. A major concern about O-2(-center dot)-mediated CDT is its tendency to induce serious oxidative damage to normal tissues, which may be addressed by using a degradable O-2(-center dot) 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 O-2(-center dot) generation and possesses a harmless-harmful switchable effect because of the photodegradation of the O-2(-center dot) scavenger iron-chlorin e6 (FeCe6). LAC-instructed substrate oxidation effectively catalyzes O-2(-center dot) production with the help of intracellular reduction, thereby promoting the conversion of Fe3+ to Fe2+, accelerating the generation of OH center dot, and inducing tumor cell apoptosis and necrosis. The introduced O-2(-center dot) scavenger FeCe6 is quickly photodegraded during irradiation, while LAC-instructed O-2(-center dot) generation proceeds as before, resulting in activatable CDT. This work not only provides the first strategy for LAC-instructed O-2(-center dot) generation but also presents new insight into activatable CDT.

Automated summary

The article introduces a new CDT agent HULK, which activates chemotherapy through LAC-guided generation of O-2(-center dot). By photodegrading the O-2(-center dot) scavenger FeCe6, it achieves a switchable effect from harmless to harmful, enhancing the therapeutic efficacy.