In situ self-assembled near-infrared phototherapeutic agent: unleashing hydrogen free radicals and coupling with NADPH oxidation

Abstract

Investigation of electron transfer (ET) between photosensitizers (PSs) and adjacent substrates in hypoxic tumors is integral to highly efficient tumor therapy. Herein, the oxygen-independent ET pathway to generate hydrogen free radicals (H˙) was established by the in situ self-assembled phototherapeutic agent d-S_T under near-infrared (NIR)-light irradiation, coupled with the oxidation of reduced coenzyme NADPH, which induced ferroptosis and effectively elevated the therapeutic performance in hypoxic tumors. The higher surface energy and longer exciton lifetimes of the fine crystalline d-S_T nanofibers were conducive to improving ET efficiency. In hypoxic conditions, the excited d-S_T can effectively transfer electrons to water to yield H˙, during which the overexpressed NADPH with rich electrons can power the electron flow to facilitate the generation of H˙, accompanied by NADP⁺ formation, disrupting cellular homeostasis and triggering ferroptosis. Tumor-bearing mouse models further showed that d-S_T accomplished excellent phototherapy efficacy. This work sheds light onto the versatile electron pathways between PSs and biological substrates.