A Integrated Molecule Based on Ferritin Nanoplatforms for Inducing Tumor Ferroptosis with the Synergistic Photo/Chemodynamic Treatment

Ferroptosis combined with photodynamic therapy (PDT) has emerged as a powerful approach to induce cancer cell death by producing and accumulating lethal reactive oxygen species (ROS) in the tumor microenvironment (TME). Despite its efficacy and safety, challenges persist in delivering multiple drugs to the tumor site for enhanced antitumor efficacy and improved tissue targeting. Hence, we designed a method of inducing ferroptosis through laser-mediated and human homologation-specific efficient activation, which is also a ferroptosis therapy with higher safety through ROS-mediated. In this study, we present a multifunctional nanoplatform, Zn-A4@FRT, featuring a integrated molecule Zn-A4, utilizing tumor-actively targeted ferritin delivery platforms to modulate the TME. In this system, Zn-A4, synthesized from zinc porphyrin (ZPP) and benzaldehyde nitrogen mustellin (BNM), serves dual roles in photo/chemodynamic therapy. Under 660 nm near-infrared laser irradiation, Zn-A4@FRT activates ZPP photosensitizers to produce toxic ROS by depleting dissolved oxygen in cancer cells, while a Fenton-like reaction enhances ROS generation. This system also induces ferroptosis through lipid peroxide accumulation, glutathione depletion, and glutathione peroxidase 4 downregulation, thereby improving the efficacy of chemodynamic therapy (CDT) and PDT in breast cancer treatment. This multifaceted strategy highlights the potential of Zn-A4@FRT as an effective approach for comprehensive cancer treatment.