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

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-MnO2) 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@MnO2-HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+, which promotes the Fenton reaction in cells to produce hydroxyl free radicals (center dot OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2O2 and enhances the production of singlet oxygen (1O2) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2-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. This work presents IR783-Fe@MnO2-HA NPs, an iron-coordinated nano-photosensitizer with a hollow double-shell design, which optimizes IR783 cellular uptake and tumor site accumulation. These nanoparticles proficiently catalyze H2O2 into O2 under acidic conditions, amplifying 1O2 production and bolstering the IR783's PDT impact. Demonstrating robust center dot OH generation, they activate ferroptosis and deplete GSH, enhancing ferroptosis therapy efficacy. image