Biomimetic Dichalcogenide‐Hybrid Nanozymes With Glutathione Peroxidase‐Like Activity for Liver Protection

ABSTRACT Glutathione peroxidase (GPX)‐mimetic nanozymes are a promising strategy to restore redox homeostasis, but many existing systems rely on metals and remain limited by cytotoxicity, poor selectivity, and susceptibility to catalytic deactivation. Inspired by the active‐site chemistry of native GPX, we designed dichalcogenide‐hybrid mesoporous silica nanoparticles (MSNs) as inorganic–organic nanozymes with tunable sulfur and selenium environments. Structure–activity analysis showed that GPX‐like performance is governed by chalcogen composition, chalcogen density, and spatial proximity of S/Se within the framework, which together regulate reversible disulfide/diselenide redox cycling and substrate access. Among the materials tested, the diselenide–hybrid framework exhibited the highest activity, with improved selectivity and biocompatibility relative to the disulfide‐hybrid analogue, and conventional metal‐based GPX mimics. Mechanistic studies indicated efficient glutathione‐dependent detoxification of peroxides and lipid peroxides through catalytically active chalcogen intermediates. In vivo, the optimized diselenide‐hybrid material protected against acetaminophen‐induced and rifampicin‐induced liver injury, reduced oxidative stress and inflammation, restored antioxidant capacity, and improved survival. It also alleviated steatosis and metabolic dysfunction in metabolic dysfunction‐associated steatotic liver disease (MASLD) models. These findings establish dichalcogenide–hybrid frameworks as effective GPX‐like nanozymes and a promising platform for the treatment of oxidative stress‐associated liver diseases.