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Inspired by the active\u2010site chemistry of native GPX, we designed dichalcogenide\u2010hybrid mesoporous silica nanoparticles (MSNs) as inorganic\u2013organic nanozymes with tunable sulfur and selenium environments. Structure\u2013activity analysis showed that GPX\u2010like 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\u2013hybrid framework exhibited the highest activity, with improved selectivity and biocompatibility relative to the disulfide\u2010hybrid analogue, and conventional metal\u2010based GPX mimics. Mechanistic studies indicated efficient glutathione\u2010dependent detoxification of peroxides and lipid peroxides through catalytically active chalcogen intermediates. In vivo, the optimized diselenide\u2010hybrid material protected against acetaminophen\u2010induced and rifampicin\u2010induced liver injury, reduced oxidative stress and inflammation, restored antioxidant capacity, and improved survival. It also alleviated steatosis and metabolic dysfunction in metabolic dysfunction\u2010associated steatotic liver disease (MASLD) models. These findings establish dichalcogenide\u2013hybrid frameworks as effective GPX\u2010like nanozymes and a promising platform for the treatment of oxidative stress\u2010associated liver diseases.<\/jats:p>","DOI":"10.1002\/adma.75439","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:35:42Z","timestamp":1792380942000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomimetic Dichalcogenide\u2010Hybrid Nanozymes With Glutathione Peroxidase\u2010Like Activity for Liver Protection"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1054-8806","authenticated-orcid":false,"given":"Fangman","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu Sichuan 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