An entropy-driven, selective copper-sequestering coordination framework for gut-restricted intervention of Wilson's disease

. 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.