Designing\nNano-Hemin for Ferroptosis-Mediated Cell\nDeath via Enzymatic Hemin Digestion

Hemin\nis a protoporphyrin complex of ferric ion which catalyzes\nH<sub>2</sub>O<sub>2</sub> degradation and produces reactive oxygen\nspecies (ROS). This ROS generation property induces oxidative stress\nto hemin-exposed cells that can lead to various situations such as\nintracellular Fenton reaction, ferroptosis, or autophagy. Therapeutic\nperformance of hemin is hindered due to low bioavailability of the\nactive monomeric form with an intact ROS generation property. Here,\nwe demonstrate a colloidal nanoparticle form of hemin (nano-hemin)\nwith a high ROS generation property and high cell uptake property.\nWe have shown that nano-hemin produces ROS inside a cell that upregulate\nheme oxygenase-1 in order to metabolize hemin. This leads to the ferroptosis-mediated\ncell death. Furthermore, we show that the ROS generation property\nof nano-hemin can be modulated to control hemin cytotoxicity for either\nferroptosis or autophagy. Our findings suggest that nano-hemin can\nbe designed with modular cytotoxicity for different therapeutic applications.