Iron-Chelating Nanoparticles Enable Cytoprotection against Ferroptosis In Vitro and In Vivo

Abstract Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and mitochondrial dysfunction, contributes to degenerative and ischemic diseases, yet strategies that simultaneously control labile iron and oxidative stress remain limited. Here, we developed mesoporous polydopamine nanoparticles (PDNs) with intrinsic antioxidant and iron-chelating properties. PDNs scavenged free radicals, reduced intracellular Fe2+ levels, preserved mitochondrial function, and rescued ferroptotic cell death in iron overload- and erastin-induced models. Untargeted metabolomics revealed that PDNs restored ferroptosis-associated metabolic profiles, including metabolites related to glutathione metabolism and energy production. In an erastin-induced muscle ferroptosis model, PDNs reduced lipid peroxidation and restored GPX4 expression. In a hindlimb ischemia model, PDNs enhanced blood perfusion and vascular recovery. Together, these findings establish PDNs as a multifunctional nanoplatform that suppresses ferroptosis through coordinated regulation of iron homeostasis, redox balance, mitochondrial function, and metabolism, offering a promising therapeutic strategy for ferroptosis-associated muscle degeneration and ischemic injury.