An Entropy-Driven, Selective Copper-Sequestering Coordination Framework for Gut-Restricted Intervention of Wilson's Disease

Aberrant Copper (Cu) accumulation drives diverse tissue pathologies as amplified in Wilson's Disease. However, current FDA-approved Cu-lowering agents (triethylenetetramine and zinc acetate) still suffer from poor ion selectivity, Cu-redistribution effect, and slow-onset with extended dosing. Herein, we propose a gut-restricted copper sequestration strategy to relieve the Cu burden based on Prussian blue analogues (PBAs). Through the synthesis and screening of 28 Zn-based PBAs crystals, we identify a trigonal, and water-deficient Zn 3 [Fe(CN) 6 ] 2 framework (ZF3) that enables the selective Zn-Cu exchange against interference from physiologically relevant ions. And we further reveal the structural determinants, i.e., crystal water and interstitial K, that govern the selectivity and kinetics of lattice Zn-Cu exchange in Zn 3 [Fe(CN) 6 ] 2 . At physiological temperatures, entropy drives partial Cu incorporation in ZF3, which proceeds uniformly, allowing efficient Cu sequestration without compromising the framework. In vivo, orally administered ZF3 is non-absorbed in the gut and eliminated via fecal excretion, concurrently promoting Cu excretion via feces without disturbing the homeostasis of other physiologically relevant ions. In Cu-overload rats, oral ZF3 effectively relieves the systemic and hepatic Cu burden and outperforms triethylenetetramine in preserving ion homeostasis in circulation and kidneys, as well as hepatoprotection. In ATP7B-deficient mice, oral ZF3 surpasses zinc acetate by both inhibiting gastrointestinal copper absorption and facilitating systemic Cu clearance, achieving a significantly faster therapeutic response. This work demonstrates the translation potential of PBAs for in vivo copper sequestration, merging the coordination frameworks with precise ion medicine.