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

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.