Nanotechnology-enabled targeting of cuproptosis in hepatocellular carcinoma: Emerging nanomedicine strategies for mitochondrial metabolic therapy

Objectives Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality, particularly in patients with advanced disease who have limited therapeutic options. This review evaluates the therapeutic potential of targeting cuproptosis, a copper-dependent form of regulated cell death, through nanotechnology-enabled strategies for HCC. Methods Relevant mechanistic and translational evidence concerning cuproptosis, copper homeostasis, mitochondrial metabolism, and copper-based nanomedicine was critically synthesized, with emphasis on HCC-specific molecular determinants, nanoengineering approaches, preclinical evidence, and barriers to clinical translation. Results Cuproptosis is initiated by intracellular copper accumulation and its interaction with lipoylated mitochondrial proteins, leading to protein aggregation, loss of iron–sulfur cluster proteins, mitochondrial dysfunction, proteotoxic stress, and cell death. Dysregulated copper homeostasis and metabolic reprogramming in HCC may create a selective vulnerability to this pathway. Copper-based nanocarriers, including copper sulfide and copper oxide nanoparticles, metal–organic frameworks, polymeric systems, and liposomal formulations, may improve tumour accumulation, controlled copper release, and mitochondrial delivery. Stimulus-responsive and actively targeted platforms may further enhance therapeutic precision while limiting systemic toxicity. However, direct evidence confirming nanoparticle-mediated cuproptosis in HCC remains limited, and substantial challenges related to biodistribution, hepatotoxicity, pharmacokinetics, manufacturing, and patient heterogeneity persist. Conclusions Cuproptosis-targeted nanomedicine represents a promising metabolic strategy for HCC. Future progress will require rigorous mechanistic validation, clinically relevant preclinical models, safety assessment, and biomarker-guided patient selection to support translation into effective precision therapies.