Cerebral amyloid angiopathy (CAA) is increasingly prevalent, and it is characterized by frequent recurrence and complex etiology. Aberrant ceruloplasmin (Cp) localization at the astrocytic endfeet, coupled with oxidative stress-induced dysregulation of iron regulatory proteins, is a central trigger of the iron dyshomeostasis that drives CAA progression. However, therapeutic strategies that specifically target iron transport regulation in astrocytes remain lacking. Here, we develop lattice-expanded Au/CeO2 with strong antioxidant capacity validated by DFT calculations. Its mesoporous architecture enables the loading of the phospholipase C inhibitor ET-18-OCH3, and further DAG peptide conjugation yields the astrocyte-targeted, biocompatible, and pluripotent nanomedicine DACe@ET. This nanoplatform stabilizes Cp at the astrocytic endfeet and restores the expression of DMT1 and FPN1. By suppressing anomalous Fe2+ influx while promoting efficient efflux and subsequent extracellular oxidation to nontoxic Fe3+, DACe@ET reestablishes a closed-loop Fe2+ export-oxidation system and restores iron homeostasis. In 3 × Tg mice, DACe@ET reduces cerebral iron deposition, decreases amyloid-β burden, attenuates neurodegeneration, and improves cognitive performance. This work demonstrates that restoring astrocytic iron trafficking hub function can serve as an effective therapeutic strategy for CAA, highlighting DACe@ET as a promising disease-modifying therapy with potential applicability to other neurological disorders marked by iron dyshomeostasis while establishing a foundation for future translational research.
Zhou et al. (Mon,) studied this question.