Promoting Oxidative Stress in Cancer Starvation Therapy by Site-Specific Startup of Hyaluronic Acid-Enveloped Dual-Catalytic Nanoreactors

Cutting off the glucose supply by glucose oxidase (GOx) has been regarded as an emerging strategy in cancer starvation therapy. However, the standalone GOx delivery suffered suboptimal potency for tumor elimination and potential risks of damaging vasculatures and normal organs during transportation. To enhance therapeutic efficacy and tumor specificity, a site-specific activated dual-catalytic nanoreactor was herein constructed by embedding GOx and ferrocene in hyaluronic acid (HA)-enveloped dendritic mesoporous silica nanoparticles to promote intratumoral oxidative stress in cancer starvation. In this nanoreactor, the encapsulated GOx served as the primary catalyst that accelerated oxidation of glucose and generation of H2O2, while the covalently linked ferrocene worked as the secondary catalyst for converting the upstream H2O2 to more toxic hydroxyl radicals (•OH) via a classic Fenton reaction. The outmost HA shell not only offered a shielding layer for preventing blood glucose from oxidation during nanoreactor transportation, thus minimizing the probable oxidative damage to normal tissues, but also imparted the nanoreactor with targeting ability for facilitating its internalization into CD44-overexpressing tumor cells. After the nanoreactor was endocytosed by target cells, the HA shell underwent hyaluronidase-triggered degradation in lysosomes and switched on the cascade catalytic reaction mediated by GOx and ferrocene. The resulting glucose exhaustion and •OH accumulation would effectively kill cancer cells and suppress tumor growth via combination of starvation and oxidative stress enhancement. Both in vitro and in vivo results indicated the significantly amplified therapeutic effects of this synergistic therapeutic strategy based on the dual-catalytic nanoreactor. Our study provides a new avenue for engineering therapeutic nanoreactors that take effect in a tumor-specific and orchestrated fashion for cancer starvation therapy.