Lipidized deferoxamine nanomedicines (DFOsomes) against iron overload.

Secondary iron overload disorders demand effective strategies for removing excess iron, yet conventional chelators such as deferoxamine (DFO) are limited by poor pharmacokinetics, low bioavailability, and dose-dependent toxicities. Here we introduce DFOsomes, a first reported lipidized DFO nanomedicine. Developed through hydrophobic modification and self-assembly into highly stable bilayer nanostructures, DFOsomes combine high chelator density with markedly improved cellular uptake and prolonged circulation. Leveraging DFO's metal-binding affinity, DFOsomes were radiolabeled with 89Zr to enable quantitative PET-MRI tracking of in vivo fate. In a systemic iron-overload model, DFOsomes markedly enhanced iron mobilization and urinary excretion compared with free DFO, and significantly reduced serum ferritin levels and organ iron deposition. To address focal brain injury, we engineered DFOsomes@Mannose, a GLUT1-targeted nanochelator that preferentially accumulates in hemorrhagic regions. In a murine intracerebral hemorrhage model, DFOsomes@Mannose suppressed ferroptosis, mitigated lipid peroxidation, and reinstated endogenous antioxidant defenses, thereby preserving neuronal architecture and expediting neurological recovery. Moreover, treatment attenuated neuroinflammation and cellular senescence, underscoring its broad-spectrum cytoprotective potential. Together, these findings establish DFOsomes as a chemically precise, safe, and broadly applicable nanochelator platform capable of addressing iron-overload disorders from systemic disease to focal brain injury, offering strong potential for clinical translation.