Oxygen-regulated enzymatic nanoplatform for synchronous intervention in glycolysis and oxidative phosphorylation to augment antitumor therapy.

Tumor cells typically undergo metabolic reprogramming to obtain substantial energy via glycolysis and oxidative phosphorylation (OXPHOS). Intervening in this reprogramming is expected to have therapeutic effects, but simultaneous intervention in these two metabolic pathways is challenging. Herein, we developed an "open-source and throttling" oxygen (O₂) modulation strategy by which we can simultaneously intervene in these two metabolic pathways. Our O₂ modulation nanoplatform (denoted as OAGO) is fabricated via the self-assembly of glucose oxidase (GOx) and oligomycin A (OA) and is coated with bacterial outer membrane vesicles (OMVs). OAGO elicits simultaneous GOx-mediated inhibition of glycolysis and OA-induced inhibition of OXPHOS. The resulting production of GOx-catalyzed hydrogen peroxide leads to oxidative stress, which exacerbates the inhibition of mitochondrial function. Meanwhile, OA reduces intratumoral O₂ consumption (i.e., the "throttling" strategy), and OMVs increase the tumor blood O₂ level (i.e., the "open-source" strategy). This results in an increase in O₂ levels for GOx catalysis, thereby exacerbating energy consumption. In addition, OMVs increase intratumoral OAGO accumulation and enable photothermal therapy in the 4T1 mouse model, which also raises the tumor blood O₂ level and benefits GOx catalysis. This synchronous intervention in two metabolic pathways alongside O₂ modulation constitutes a promising approach for efficient antitumor therapy.