A Tumor‐Specific Platform of Peroxynitrite Triggering Ferroptosis of Cancer Cells

Abstract Peroxynitrite (ONOO − ) is a potent oxidant and nucleophile participating in a variety of pathophysiological processes as well as playing a major role in cancer therapy. However, the intracellular environment of solid tumors severely restricts the production of ONOO − , which leads to an unsatisfactory anticancer effect. Here, a tumor‐specific platform for ONOO − generation, prepared by linking a type I photosensitizer with a GSH‐responsive NO donor, is constructed to overcome the tumor hypoxic microenvironment and enhance treatment efficiency (NBS‐2S‐NO). Responding to the overexpressed glutathione (GSH) within tumors, NBS‐2S‐NO can selectively induce ONOO − generation after a cascade including red light irradiation causing superoxide radical (O 2 •− ) production, GSH‐triggered NO release, and fast reaction between O 2 •− and NO. The generated ONOO − can cause oxidative damage to tumor cells, induce lipid peroxidation (LPO) during the cell death process and finally cause ferroptosis. Both in vitro and in vivo outcomes demonstrate the notable anticancer ferroptosis efficacy of this platform, suggesting not only an effective ferroptosis strategy for the design of new photosensitizers but also a worthy of reference for antioxidant regulation to enhance the oxidative damage during the tumor treatment process.