Dual-Release Free Iron and Breakdown of Ferroptosis Defenses to Achieve Ferroptosis Cascade Storms for Potent Antitumor Therapy

Ferroptosis is a newly identified type of regulated cell death characterized by iron-dependent lipid peroxidation. Among the main ferroptosis-suppressing systems, the dihydroorotate dehydrogenase (DHODH)- ubiquinone axis is closely related to mitochondria and energy metabolism, implying that the axis protects cells from oxidative stress damage via the maintenance of redox homeostasis. However, ferroptosis initiation requires a suitable oxidative environment and a breakthrough in redox homeostatic limitations by ferroptosis-suppressing systems. Hence, the nanoparticles are rationally engineered to achieve efficient ferroptosis induction by releasing dual-release free iron and disrupting ferroptosis-suppressing systems. Atovaquone (ATO)-loaded hollow mesoporous etching zeolitic imidazolate framework-67 double-coated iron oxide/calcium phosphate (Fe 3 O 4 /CaP) is conjugated with polyethylene glycol. The external double-coated Fe 3 O 4 /CaP structure enhances the efficiency of multiple reactive oxygen species (ROS) generation promoting oxidative stress. Still, it achieves free iron dual-release to increase the content of unstable iron pools for igniting the ROS storm and lipid peroxidation spark. The release of ATO not only affects the energy metabolism of the mitochondrial respiratory chain by binding to complex III but also downregulates DHODH to restrict the ubiquinol system to disrupt the ferroptosis-suppressing systems. Therefore, the design of this composite nanomedicine provides an approach for inducing ferroptosis and a theoretical basis for clinical ferroptosis anti-tumor trials.