A platinum nanourchin-based multi-enzymatic platform to disrupt mitochondrial function assisted by modulating the intracellular H 2 O 2 homeostasis.

Endogenous H ₂ O ₂ sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable H ₂ O ₂ 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 H ₂ O ₂ -rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn ^2+/3+ . The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O ₂ replenishment through Pt-catalyzed decomposition of H ₂ O ₂ . Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn ^2+/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 H ₂ O ₂ level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular H ₂ O ₂ balance during H ₂ O ₂ -depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction.
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