Nanozyme hydrogel for enhanced alkyl radical generation and potent antitumor therapy

Alkyl radicals (R˙), which do not rely on oxygen generation for causing cellular stress, have been applied in tumor treatment, but a large amount of glutathione (GSH) in the tumor cells reacts with alkyl radicals, thereby reducing their antitumor effect. In this study, an enhanced alkyl radical generation system responsive to near-infrared light was designed. The alkyl radical trigger 2,2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) and nanozyme pyrite (FeS₂) were encapsulated in agarose hydrogel to prepare the AIPH-FeS₂-hydrogel (AFH) system. FeS₂ can be used as a photothermal agent to convert near-infrared light energy into heat energy, leading to the dissolution of the hydrogel. AIPH is simultaneously induced to produce alkyl radicals. FeS₂ can also be used as an oxidative stress amplifier to reduce intracellular GSH content, thereby boosting the therapeutic effect of alkyl radicals. Eventually, the oxygen-independent free radicals generated by the AFH system under near-infrared laser irradiation and photothermal treatment can kill cancer cells through the synergistic oxidation/photothermal effect. The AFH system developed herein provides new insights into enhancing the therapeutic effect of alkyl radicals.