A platinum nanourchin-based multi-enzymatic platform to disrupt mitochondrial function assisted by modulating the intracellular H2O2 homeostasis.

ABSTRACT

Endogenous H2O2 sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable H2O2 supply from tumor microenvironment (TME). Herein, a platinum (Pt) nanourchin-based multi-enzymatic platform (referred to PGMA) is established by surface conjugation of glucose oxidase (GOx) capped with manganese carbonyl (MnCO) and loading 3-amino-1,2,4-triazole (3-AT). The mild acidic and H2O2-rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn2+/3+. The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O2 replenishment through Pt-catalyzed decomposition of H2O2. Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn2+/3+ couple-mediated Fenton-like reaction. Hence, CO release-initiated gas therapy, glucose exhaustion-induced tumor starvation and ROS-triggered chemodynamic therapy are committed to realizing a combinatorial disruption effect on mitochondrial function. Importantly, the released 3-AT can inhibit the activity of endogenous catalase, which effectively elevates the intracellular H2O2 level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular H2O2 balance during H2O2-depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction.