Oral Engineered Extracellular Vesicles Based on Ion Exchange Strategy for Multipronged Management of Wilson's Disease Complicated with Reproductive Dysfunction Therapy

Abstract Wilson's disease (WD), as a typical disease of excessive Cu 2+ deposition, is characterized by disorders of copper metabolism in the brain and thereby damaging the reproductive system. Conventional interventions using copper chelators can temporarily reduce intracellular copper (in‐copper), but continuous re‐entry of extracellular copper (ex‐copper) into cells results in suboptimal therapy. Effective therapy requires multipronged copper metabolism management. Here, an orally administered, engineered Ganoderma‐derived extracellular vesicle (CZGE) is developed for synergistic in/ex‐copper regulation. Specifically, CZGE is designed by co‐fusing Ganoderma‐derived extracellular vesicle (GEVs) and targeted nanomicelles containing zinc‐curcumin (Zn‐Cur) complex (ZCNs). CZGE, with β ‐glucan‐enriched GEVs and kisspeptin‐10‐modified ZCNs, can effectively penetrate intestinal and brain barriers after oral administration to target hypothalamic neurons.After internalization, Zn‐Cur released from CZGE replaces excess Cu 2+ to form copper‐curcumin (Cu‐Cur) and release Zn 2+ via ion exchange. Cu‐Cur reduces in‐copper and neuroinflammation via the Nrf2/NLRP3 pathway, while Zn 2+ inhibits ex‐copper influx by activating zinc transporter 1. In WD mice, CZGE alleviates hypothalamic copper deposition, activates ERK1/2 phosphorylation, and repairs reproductive dysfunction by modulating the hypothalamic‐pituitary‐testicular axis. It first reveals a targeted nanomedicine based on ion exchange that multipronged management in‐copper and ex‐copper, offering a promising therapeutic strategy for addressing WD with reproductive dysfunction.