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

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 self-assembled phototherapeutic agent -S 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 -S nanofibers were conducive to improving ET efficiency. In hypoxic conditions, the excited -S 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 -S accomplished excellent phototherapy efficacy. This work sheds light onto the versatile electron pathways between PSs and biological substrates.