Metabolomic and Proteomic Analyses Unveil That Polyethylene Glycol–Polycaprolactone-Loaded Curcumin Nanoparticles Induce Mitochondrial Dysfunction and Metabolic Reprogramming to Suppress Melanoma Growth

Melanoma is highly dependent on cellular metabolism, but current treatments show limited effectiveness. Despite the promising antitumor properties of curcumin, its clinical utility is limited by its poor bioavailability and potential systemic toxicity. To address these challenges, we formulated curcumin-loaded polyethylene glycol–polycaprolactone (PEG–PCL) nanoparticles, denoted as PEG–PCL@Cur. We employed omics technologies to investigate their impact on melanoma at the molecular level. In vitro studies revealed that PEG–PCL@Cur notably suppressed the growth, movement, and invasiveness of A375 melanoma cells in a dose-dependent manner. Untargeted metabolomics identified 347 metabolites that were significantly altered. A decrease in fumaric acid levels indicated the suppression of oxidative phosphorylation and a shift in metabolism. Proteomics further confirmed the downregulation of key mitochondrial proteins, such as SDHA, pointing to mitochondrial dysfunction. Mechanistically, PEG–PCL@Cur increased reactive oxygen species (ROS) production by raising NADH levels and inhibiting SDHA expression. This led to a reduction in the level of fumaric acid production and a disruption of the tricarboxylic acid (TCA) cycle. Additionally, PEG–PCL@Cur hindered the generation of inorganic phosphate (Pi), resulting in a decreased level of ATP production. These metabolic changes promoted apoptosis and enhanced melanoma cell death. In vivo, PEG–PCL@Cur significantly curtailed tumor growth in a melanoma xenograft model and displayed an enhanced biocompatibility. Histological analysis showed extensive tumor necrosis, diminished proliferation markers, and elevated levels of apoptosis indicators. Overall, our integrated metabolomic and proteomic approach highlights how PEG–PCL@Cur targets SDHA-mediated metabolic reprogramming and mitochondrial dysfunction. This discovery positions PEG–PCL@Cur as a promising nanoplatform for melanoma therapy and offers valuable insights into the development of targeted nanomedicines.