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

Wilson's disease (WD), as a typical disease of excessive Cu2+ 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 Cu2+ to form copper-curcumin (Cu-Cur) and release Zn2+ via ion exchange. Cu-Cur reduces in-copper and neuroinflammation via the Nrf2/NLRP3 pathway, while Zn2+ 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.