A nanoenzyme reactor fueled by a High-Glucose microenvironment for augmented diabetic tumor therapy

Diabetes is recognized as an independent risk factor for the onset and advancement of cancer. However, there has been limited emphasis on investigating the diabetic tumor microenvironment (TME) and harnessing its inherent microenvironmental distinctions to facilitate tumor ablation. The management of cancer with diabetes is often challenging. Herein, an activatable hollow mesoporous manganese silicate (H-Mn)/indocyanine green (ICG)/glucose oxidase (GOX) nanoenzyme (H-MIG) was developed for diabetic tumor therapy. This micro-reactor consumes glucose to trigger a sequential cascade reaction to biologically amplify the antitumor effect under hyperglycemia conditions. H-Mn degrades within the TME, releasing O2 and Mn2+. The presence of O2 promotes GOX-induced glucose consumption, leading to the subsequent production of H2O2. This glucose-fueled oxidation also provides reactants for chemodynamic therapy, as H2O2 and Mn2+ in the TME subsequently undergo a Fenton-like reaction. In addition, by inhibiting the expression of the heat shock protein 90, which is highly expressed in diabetic TME, GOX enhances ICG-guided mild-temperature photothermal therapy. In vitro and in vivo experiments demonstrated that the domino effect fueled by this high-glucose TME improves anticancer efficacy. By exploiting the complementary cascade reactions, this endogenous enzyme-based strategy could inspire the design of more promising advanced platforms for more efficient diabetic cancer therapy.