GSH‐Responsive Organosilica Hybrid Nanosystem as a Cascade Promoter for Enhanced Starvation and Chemodynamic Therapy

Glucose oxidase (GOD)-mediated starvation therapy (ST) that causes intratumoral glucose depletion is a promising strategy for tumor treatment. However, the ultimate efficacy is inevitably limited by tumor hypoxia, as oxygen is a key component in the consumption of glucose by GOD. In this study, a kind of glutathione (GSH)-responsive organosilica hybrid micelles loaded with Mn3 O4 and GOD (denoted as Mn3 O4 @PDOMs-GOD) is ingeniously designed for enhanced ST and chemodynamic therapy (CDT). Specifically, the internalized Mn3 O4 @PDOMs-GOD in tumor cells consumes intracellular glucose and oxygen (O2 ) under the catalysis of GOD to generate hydrogen peroxide (H2 O2 ), which is subsequently decomposed by Mn3 O4 to liberate O2 . This cyclically regenerated O2 will form a virtuous cycle of O2 and H2 O2 compensation to enhance the ST outcome. Meanwhile, Mn3 O4 can oxidize and deplete the overexpressed GSH in the tumor microenvironment (TME) to release Mn2+ , which then catalyzes H2 O2 into highly toxic hydroxyl radicals (·OH) to accomplish chemodynamic therapy (CDT). Both in vitro and in vivo experiment results demonstrate the significant antitumor efficacy of Mn3 O4 @PDOMs-GOD by the cooperatively enhanced ST and CDT, suggesting the feasibility to develop promising therapeutic platforms with higher treatment efficacies.