Neutrophil-mimetic hybrid liposome with ROS cascade amplification for synergistic ferroptosis-photodynamic therapy of breast cancer

Photodynamic therapy (PDT) and ferroptosis therapy have received extensive attention in breast cancer treatment. PDT induced apoptosis of tumor cells by producing a large amount of reactive oxygen species (ROS) under laser irradiation. Differently, ferroptosis therapy exerts its antitumor effect by inducing excessive accumulation of lipid peroxides on tumor cell membranes. Based on that, ROS produced by PDT may promote ferroptosis in tumor cells, and ferroptosis therapy is expected eliminate apoptosis-resistant tumor cells. Therefore, a synergistic ferroptosis-photodynamic therapy will be more effective and more potential in breast cancer treatment. Considering PDT has the characteristic of producing ROS, and neutrophil has a natural tendency to ROS, a neutrophil-mimetic hybrid liposome (CR-NML) was designed for co-delivery of the photosensitizer Ce6 and the ferroptosis inducer RSL3. CR-NML targeted tumor through the ROS tendency of neutrophil and the enhanced permeability and retention (EPR) effect of liposome, then induced both apoptosis and ferroptosis in tumor cells, which increased ROS level and finally realized ROS cascade amplification. The synergistic ferroptosis-photodynamic therapy demonstrated significant therapeutic efficacy in 4T1 tumor bearing mice, which provided a promising strategy for breast cancer treatment.