Local glycolysis-modulating hydrogel microspheres for a combined anti-tumor and anti-metastasis strategy through metabolic trapping strategy

Anti-glycolysis is well-recognized for inhibition of tumor proliferation. However, tumor metabolic heterogeneity confers great challenges in the therapeutic efficacy of glycolysis inhibitors. Here, a metabolic trapping strategy was employed to avoid metabolism heterogeneity in tumors. Unlike usual glycolysis inhibition, the glycolysis level was first promoted. Then excessive metabolite of lactate was transformed into H 2 O 2 and hydroxyl radical by lactate oxidase (LOX) and MIL-101 (Fe) nanoparticles (MF). Finally, the ATP production was inhibited, and the tumor was suppressed by the generation of toxic reactive oxygen species (ROS). We realized this strategy via methacrylated gelatin (GelMA) hydrogel microspheres, co-loaded with metformin (MET) and LOX@MF. The results showed that MET was completely released within 2 h, followed by most LOX@MF released within 72 h. LOX@MF and MET synergistically suppressed tumor proliferation and angiogenesis both in vitro and in vivo . Compared with control, the primary tumor volume was reduced by 75.7 %, and the average number of lung metastasis nodules decreased from 15.5 to 1.0. Regarding the metabolism, higher glycolytic enzymes expressions were observed initially, followed by lower lactate and vascular endothelial growth factor (VEGF), and finally elevated ROS levels. Overall, our study provides new insights to improve metabolism heterogeneity-limited metabolic cancer therapy.