Multifunctional Nanotherapeutic Platform: Metformin Potentiates Ce6/GOX-based Targeted Synergistic Therapy for Colorectal Cancer

Colorectal cancer (CRC) is the third most prevalent malignancy globally. Its tumor microenvironment (TME) heterogeneity and chemotherapy resistance compromise the efficacy of conventional treatments such as surgery and chemotherapy. This study developed a multifunctional nanotherapeutic platform by synthesizing mesoporous silica nanoparticles (MSNs) via a modified Stöber method. The carboxylated MSN surface was sequentially loaded with metformin (Me), chlorin e6 (Ce6), and glucose oxidase (GO X ), constructing an Me/Ce6@MSN-GO X (MCMG) nanosystem. The synthesized MSNs demonstrated excellent porosity, pore volume, and high loading capacity. In vitro and in vivo studies showed that MCMG reversed the Warburg effect via the AMPK/ACC/mTOR axis, reprogrammed tumor energy metabolism, and enhanced GO X -induced starvation therapy and Ce6-based photodynamic therapy (PDT). MCMG also alleviated TME hypoxia by suppressing HIF-1α expression, inducing an approximately 2-fold increase in intracellular reactive oxygen species levels and culminating in a 71% tumor inhibition rate in vivo. This platform integrated Me’s metabolic regulation with Ce6-mediated PDT and GO X -driven starvation therapy to achieve synergistic CRC eradication. MCMG enables multifunctional theranostics through synergistic mechanisms (metabolic modulation, oxidative damage, and nutrient deprivation) coupled with fluorescence imaging capabilities, presenting a novel strategy for CRC treatment.