Hyperbaric Oxygen Activates Enzyme-Driven Cascade Reactions for Cooperative Cancer Therapy and Cancer Stem Cells Elimination.

Tumor starvation induced by intratumor glucose depletion emerges as a promising strategy for anticancer therapy. However, its antitumor potencies are severely compromised by intrinsic tumor hypoxia, low delivery efficiencies, and undesired off-target toxicity. Herein, a multifunctional cascade bioreactor (HCG), based on the self-assembly of pH-responsive hydroxyethyl starch prodrugs, copper ions, and glucose oxidase (GOD), is engineered, empowered by hyperbaric oxygen (HBO) for efficient cooperative therapy against aggressive breast cancers. Once internalized by tumor cells, HCG undergoes disassembly and releases cargoes in response to acidic tumor microenvironment. Subsequently, HBO activates GOD-catalyzed oxidation of glucose to H 2 O 2 and gluconic acid by ameliorating tumor hypoxia, fueling copper-catalyzed •OH generation and pH-responsive drug release. Meanwhile, HBO degrades dense tumor extracellular matrix, promoting tumor accumulation and penetration of HCG. Moreover, along with the consumption of glucose and the redox reaction of copper ions, the antioxidant capacity of tumor cells is markedly reduced, collectively boosting oxidative stress. As a result, the combination of HCG and HBO can not only remarkably suppress the growth of orthotopic breast tumors but also restrain pulmonary metastases by inhibiting cancer stem cells. Considering the clinical accessibility of HBO, this combined strategy holds significant translational potentials for GOD-based therapies.