Hepatocellular Carcinoma Targeted Thermosensitive Cu²⁺ Liposomes Based on the Cuproptosis Mechanism

Cuproptosis is characterized by elevated intracellular copper concentrations that disrupt copper homeostasis and impair the tricarboxylic acid cycle, ultimately causing cell death. However, the lack of targeted intervention for intracellular copper may induce systemic side effects, hindering the application of cuproptosis in tumor therapy. Herein, we constructed a targeted copper ion delivery system (Cu-Lip-Gal(H)) based on galactose-modified thermosensitive liposomes, combined with local tumor hyperthermia targeted copper delivery into hepatocellular carcinoma (HCC) cells. Cu-Lip-Gal showed excellent physicochemical properties and 42°C thermosensitive release, with 64.67% ± 2.52% cumulative release within 0.5 h. The Cu-Lip-Gal(H) group reduced HepG2 and Huh7 cell viability to 24.48% ± 3.31% and 18.00% ± 3.18%, respectively; it exhibited 5.8-fold higher intracellular copper concentration in HepG2 cells and 5.2-fold higher in Huh7 cells. In nude mouse xenografts, Cu-Lip-Gal(H) achieved a tumor inhibition rate of 86.7% ± 1.9% without obvious histopathological changes in major organs but significantly increased necrotic cells in tumors along with the highest FDX1 expression levels observed in this study. These findings provide new insights into cuproptosis-based copper ion delivery systems for HCC treatment.