Designing Nano-Hemin for Ferroptosis-Mediated Cell Death via Enzymatic Hemin Digestion

degradation and produces reactive oxygen species (ROS). This ROS generation property induces oxidative stress to hemin-exposed cells that can lead to various situations such as intracellular Fenton reaction, ferroptosis, or autophagy. Therapeutic performance of hemin is hindered due to low bioavailability of the active monomeric form with an intact ROS generation property. Here, we demonstrate a colloidal nanoparticle form of hemin (nano-hemin) with a high ROS generation property and high cell uptake property. We have shown that nano-hemin produces ROS inside a cell that upregulate heme oxygenase-1 in order to metabolize hemin. This leads to the ferroptosis-mediated cell death. Furthermore, we show that the ROS generation property of nano-hemin can be modulated to control hemin cytotoxicity for either ferroptosis or autophagy. Our findings suggest that nano-hemin can be designed with modular cytotoxicity for different therapeutic applications.