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 Mn 3 O 4 and GOD (denoted as Mn 3 O 4 @PDOMs-GOD) is ingeniously designed for enhanced ST and chemodynamic therapy (CDT). Specifically, the internalized Mn 3 O 4 @PDOMs-GOD in tumor cells consumes intracellular glucose and oxygen (O 2 ) under the catalysis of GOD to generate hydrogen peroxide (H 2 O 2 ), which is subsequently decomposed by Mn 3 O 4 to liberate O 2 . This cyclically regenerated O 2 will form a virtuous cycle of O 2 and H 2 O 2 compensation to enhance the ST outcome. Meanwhile, Mn 3 O 4 can oxidize and deplete the overexpressed GSH in the tumor microenvironment (TME) to release Mn 2+ , which then catalyzes H 2 O 2 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 Mn 3 O 4 @PDOMs-GOD by the cooperatively enhanced ST and CDT, suggesting the feasibility to develop promising therapeutic platforms with higher treatment efficacies.