Shu Feng, Ying Xuan, Hong Jin, Meng Cui, Xinyue Meng, Jun Liao, Jianwei Feng
Hepatocellular carcinoma (HCC) remains a formidable challenge due to profound heterogeneity, recurrence, and pervasive therapeutic resistance, creating a significant unmet clinical need. Engineered nanozymes, nanomaterials with intrinsic catalytic activities, have emerged as a transformative paradigm. Unlike passive nanocarriers, nanozymes function as active therapeutic agents. Their prowess is predicated on catalytically manipulating the tumor microenvironment (TME), enabling localized ROS generation, inducing regulated cell death, and remodeling the immunosuppressive TME. This review systematically delineates the principles and potential of nanozyme strategies for HCC, focusing on catalytic therapy, nanozyme-enhanced immunotherapy, photothermal therapy, and integrated combination platforms, highlighting their capacity for synergistic antitumor effects. The review also critically discusses formidable challenges spanning metabolic heterogeneity, TME-driven immunosuppression, and biocompatibility hurdles that impede clinical translation. This work provides critical insights for the rational design of next-generation nanozymes and accelerating their integration into future multidisciplinary HCC treatment frameworks.