A Redox‐Triggered Polymeric Nanoparticle for Disrupting Redox Homeostasis and Enhanced Ferroptosis

Abstract Cancer cells possess an efficient redox system, enabling them to withstand oxidative damage induced by treatments, especially in hypoxia areas and ferroptosis can disrupt redox homeostasis in cancer cell. Herein, GSH‐sensitive nanoparticles are constructed that induce ferroptosis by long‐lasting GSH depletion and enhanced PDT. Carbonic anhydrase IX inhibitor, protoporphyrin IX (Por) complexed with Fe and epirubicin (EPI) are grafted to hyaluronic acid (HA) via disulfide bonds to obtain HSPFE and loaded xCT inhibitor SAS for fabricating SAS@HSPFE which is actively targeted to deep hypoxic tumor cells, and explosively releasing EPI, Por‐Fe complex and SAS due to at high GSH concentration. Specifically, SAS inhibited the GSH biosynthesis, and the generation of ROS by Por and the involvement of Fe²⁺ in the Fenton reaction jointly facilitates oxidative stress. Besides, Fe²⁺ reacted with excess H₂O₂ to produce O₂, which continuously fuels PDT. GPX4 and SLC7A11 related to antioxidant defense are down‐regulated, while ACSL4 and TFRC promoting lipid peroxidation and ROS accumulation are up‐regulated, which enhanced ferroptosis by amplifying oxidative stress and suppressing antioxidant defense. SAS@HSPFE NPs revealed highly efficient antitumor effect in vivo study. This study provides a novel approach to cancer treatment by targeting redox imbalance.