Nanoparticle-Mediated Dual Regulation of Glycolysis and Oxidative Phosphorylation Selectively Overcomes Metabolic Plasticity in Hepatocellular Carcinoma

Conventional cancer treatments have shown limited efficacy and substantial side effects, often allowing cancer cells to survive during treatment. To address these challenges, more recent therapeutic approaches have focused on targeting cancer-specific metabolic pathways. Cancer cells exhibit a metabolic shift toward aerobic glycolysis for energy production, even under oxygen-rich conditions, which is a hallmark known as the Warburg effect. Liver cancer exhibits rapid metabolic activity with a strong dependence on both glycolysis and oxidative phosphorylation (OXPHOS). Although glycolysis inhibition has been explored, metabolic compensation via the adsorption of OXPHOS often undermines therapeutic efficacy. To overcome this limitation, we developed a nanoscale dual-metabolic inhibition platform using PEGylated PLGA (PLGA-PEG) nanoparticles to encapsulate shikonin (SHK; glycolysis inhibitor) or atovaquone (ATO; OXPHOS inhibitor) via a double-emulsion solvent evaporation method. The resulting uniformly dispersed nanoparticles exhibit enhanced solubility, stability, and tumor accumulation through the enhanced permeability and retention (EPR) effect. Separate nanoencapsulation enabled precise control of the SHK:ATO ratio, which was optimized for selective cytotoxicity toward HepG2 cells while minimizing toxicity to normal fibroblasts. In vitro, the combination disrupted glycolytic and mitochondrial metabolism and induced apoptosis. Building on these results, in vivo studies using an orthotopic HCC model confirmed efficient tumor accumulation, marked tumor suppression, and reduced liver toxicity. This study presents a nanoparticle-enabled dual metabolic inhibition strategy that achieves potent antitumor efficacy while overcoming the limitations of conventional cancer therapies and single-pathway metabolic inhibitors, offering a promising nanomedicine approach for HCC.