Glycopolymer-Based Hydrogels Impair Energy Metabolism via Delivering Mannose and Depleting Glucose for Tumor Suppression

Carbohydrates serve as a key biomacromolecule, not only as the major building blocks in living organisms, but also as intermediates in energy metabolism via glycolysis. The quest for developing a carbohydrate-based macromolecular system to interfere with aberrant energy metabolism of tumors is a challenging topic. Here we report a class of artificial glycopolymers containing phenolic hydroxyl-functionalized segments that can be cross-linked to form hydrogels by the enzymatic cascade reaction using glucose oxidase (GOD) and horseradish peroxidase (HRP). Glycopolymer-based hydrogels can deliver and sustainably release the antiglycolytic agent mannose at the tumor site; meanwhile, glucose is exhausted gradually during the course of gelation. Glucose uptake and hyperactive glycolysis of tumor cells are concurrently blocked by the enzyme cascade and mannose, respectively, as validated by synergistic tumor suppression in vitro. Finally, the superiority of glycopolymer-based hydrogels loading mannose and enzyme cascade is evaluated in a murine tumor model, demonstrating the ability to impair energy metabolism and retard tumor growth. This work allows glycopolymer-based biomaterials to be promising in intervening energy metabolism for tumor eradication.