Novel Carrier‐Free Nanomedicine for Regulating Macrophage Phenotype to Amplify Anti‐Tumor Photoimmunotherapy

Abstract Photoimmunotherapy presents a significant development potential both in inducing anti‐tumor immunity and regulating the tumor microenvironment. However, the immunosuppressive tumor microenvironment (ITM) severely impedes the infiltration and functional activity of immune cells, while conventional immunotherapy strategies often fall short of inducing a potent and sustained anti‐tumor immune response. Here, stable carrier‐free self‐assembled nanoparticles (BC NPs) based on π – π stacking, hydrogen bonding, and hydrophobic interactions is developed using photosensitizer Ce6 and Baicalein, a natural product isolated from Scutellaria baicalensis. Baicalein amplifies photodynamic therapy to activate programmed ferroptosis in tumor cells by reducing the level of glutathione (GSH) in tumors. Simultaneously, Baicalein can promote the polarization of M1 macrophages in the TME, leading to the production of TNF‐α and anti‐tumor effects, which synergize with immunogenic cell death induced by photodynamic therapy to reshape the immunosuppressive tumor microenvironment Glutathione and induce long‐lasting and powerful anti‐tumor immune responses. In summary, this work provides an effective carrier‐free photoimmunotherapy nanomedicine.