Manganese‐Copper Co‐Doped NiFe‐LDH Nanosheets toward Multi‐Enzymatic Activities and Cascaded Synergistic Anti‐Liver Tumor Therapy

Abstract Primary liver cancer remains a significant global health challenge, with the majority of patients diagnosed at an unresectable stage, further complicated by liver dysfunction due to cirrhosis. To address these clinical hurdles, nanozyme‐based catalytic therapy has emerged as a promising strategy. However, its therapeutic efficacy is often limited by self‐protective mechanisms associated with the tumor microenvironment (TME), particularly the overexpression of glutathione (GSH) and hypoxia‐induced metabolic adaptation. In this study, a quaternary medium‐entropy layered double hydroxide (LDH) nanozyme, denoted as NiFeMnCu‐LDH is developed. This nanozyme exhibits peroxidase‐like, catalase (CAT)‐like, and oxidase‐like activities, facilitating the cascade generation of reactive oxygen species (ROS). Simultaneously, the oxygen produced by CAT mitigates hypoxia, while the glutathione peroxidase‐like 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‐enzyme synergy for translational applications.