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To address these clinical hurdles, nanozyme\u2010based catalytic therapy has emerged as a promising strategy. However, its therapeutic efficacy is often limited by self\u2010protective mechanisms associated with the tumor microenvironment (TME), particularly the overexpression of glutathione (GSH) and hypoxia\u2010induced metabolic adaptation. In this study, a quaternary medium\u2010entropy layered double hydroxide (LDH) nanozyme, denoted as NiFeMnCu\u2010LDH is developed. This nanozyme exhibits peroxidase\u2010like, catalase (CAT)\u2010like, and oxidase\u2010like activities, facilitating the cascade generation of reactive oxygen species (ROS). Simultaneously, the oxygen produced by CAT mitigates hypoxia, while the glutathione peroxidase\u2010like activity drives the depletion of tumor antioxidants, effectively reprogramming the TME. Further in vitro experiments demonstrated that efficient production of ROS and scavenging of GSH induced substantial apoptosis in liver cancer cells. Additionally, mouse liver tumor models showed robust inhibition of tumor growth without systemic toxicity. This findings provide a framework for the precise engineering of nanozymes in advanced liver cancer treatment, addressing critical barriers within the TME and offering valuable insights into a mimetic multi\u2010enzyme synergy for translational applications.<\/jats:p>","DOI":"10.1002\/adhm.202503072","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T05:48:46Z","timestamp":1754027326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Manganese\u2010Copper Co\u2010Doped NiFe\u2010LDH Nanosheets toward Multi\u2010Enzymatic Activities and Cascaded Synergistic Anti\u2010Liver Tumor Therapy"],"prefix":"10.1002","volume":"14","author":[{"given":"Hongwei","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine\/Clinical Laboratory Medicine Research Center West China Hospital Sichuan University  Chengdu Sichuan 610041 China"},{"name":"Division of Liver 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