Astrocyte-Targeted Nanotherapeutics Modulate Iron Homeostasis in Cerebral Amyloid Angiopathy by Restoring the Astrocytic Trafficking Hub Function.

Abstract

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.