Study of Iron Complex Photosensitizer with Hollow Double‐Shell Nano Structure Used to Enhance Ferroptosis and Photodynamic Therapy

Abstract Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H‐MnO 2 ) with double‐shell nanostructure is designed to contain iron coordinated cyanine near‐infrared dye IR783 (IR783‐Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783‐Fe@MnO 2 ‐HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe 3+ and IR783 in acidic TME. First, Fe 3+ consumes glutathione to produce Fe 2+ , which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO 2 catalyzes the production of O 2 from H 2 O 2 and enhances the production of singlet oxygen ( 1 O 2 ) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783‐Fe@MnO 2 ‐HA nano‐photosensitizers have exhibited tumor‐targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.