Ferritin/Ferroportin-Regulating Nanoparticles Boosting Intracellular Free Iron for Enhanced Ferrotherapy

Ferroptosis therapy efficacy of cancers suffers from relatively low concentrations of intracellular free iron ions due to the efficient regulation of iron through storage in ferritin and efflux via ferroportin (FPN). In this study, a ferritin/ferroportin-hijacking nanoplatform (Fe₃O₄-ART@MM-Hep) containing artemisinin (ART) and hepcidin (Hep) is fabricated to boost intracellular free iron ions and induce reactive oxygen species (ROS) storm. Once the tumor site is reached, the hepcidin targeted binds to FPN and triggers the internalization and degradation of FPN, blocking the efflux of intracellular iron ions. Meanwhile, artemisinin induces lysosomal degradation of ferritin, liberating the endogenous iron. Combined with exogenous iron supplemented by Fe₃O₄, the nanoplatform facilities the generation of ROS. What's more, the released Fe²⁺ catalyzes artemisinin to generate carbon-centered free radicals, further enhancing tumor killing ability. All of the above strategies trigger an ROS storm in tumor cells and indicate a promising platform for high-performance ferrotherapy.