Dual-Loaded Curcumin and Phenformin Copolymer Micelles for Targeted Colorectal Cancer Therapy via Mitochondrial Stress and Metabolic Modulation

Curcumin, a natural polyphenol from Curcuma longa, exhibits potent anti-cancer properties against colorectal cancer (CRC), yet its poor solubility and rapid systemic clearance severely limit clinical translation and overall therapeutic efficacy in patients. To overcome these challenges, curcumin-loaded copolymer micelles were rationally engineered, significantly improving solubility, pharmacokinetic stability, tumor-specific accumulation, and efficient cellular uptake in CRC cells. Phenformin, a mitochondrial complex I inhibitor with reported chemopreventive activity in CRC, was co-encapsulated to develop a dual-targeting nanomedicine with enhanced precision, specificity, and potential synergistic anti-cancer effects. In vitro, curcumin micelles alone moderately inhibited proliferation and migration of HCT116 cells, whereas curcumin/phenformin co-loaded micelles were required to elicit comparable effects in CT26 cells, reflecting distinct cell line-specific metabolic dependencies on glycolysis and oxidative phosphorylation. Mechanistically, the dual-loaded formulation induced overproduction of reactive oxygen species and pronounced mitochondrial dysfunction, highlighting markedly enhanced oxidative and energetic stress. In subcutaneous CRC models, curcumin/phenformin micelles exhibited significantly superior anti-tumor efficacy compared with single-agent or unloaded treatments. Taken together, this dual-targeting nanomedicine not only enhances curcumin bioavailability, systemic stability, and tumor-specific delivery but also selectively modulates tumor metabolism and triggers mitochondrial stress, providing a highly promising, versatile, and translationally relevant therapeutic strategy for colorectal cancer treatment.