Abstract: Glucose oxidase (GOx) catalyzes the oxidation of glucose to gluconic acid and hydrogen peroxide (H 2 O 2 ), while horseradish peroxidase (HRP) converts H 2 O 2 into cytotoxic hydroxyl radicals ( • OH) under acidic conditions, such as those in lysosomes. Harnessing this tandem enzymatic activity offers a promising strategy to exacerbate tumor hypoxia and induce cancer cell death. Herein, we report the synthesis of hollow, porous organic nanocapsules (HPOCs; average diameter ∼145 nm, wall thickness ∼11 nm) via an inverse mini-emulsion technique using functionalized diamine and tetracarbaldehyde precursors. These nanocapsules coencapsulate GOx and HRP while acting as size-exclusion membranes, allowing selective diffusion of small molecules while retaining the enzymes. Confocal studies with BODIPY-labeled GOx and Cy5-labeled HRP ensure the encapsulation of both enzymes within the HPOCs and are found to be localized in the lysosome. The HPOCs exhibit excellent biocompatibility and, under hypoxic conditions, trigger substantial cancer cell apoptosis (∼75% cell death) and G 2 /M cell cycle arrest. Control nanocapsules lacking either or both enzymes show negligible therapeutic effect, underscoring the synergistic mechanism. This work presents a proof-of-concept for two-enzyme-loaded HPOCs as an effective platform for synergistic, hypoxia-amplified cancer therapy.
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