Glucose oxidase-amplified CO generation for synergistic anticancer therapy via manganese carbonyl-caged MOFs.

Carbon monoxide (CO) as one of the therapeutic gaseous molecules has been widely applied for treating various diseases, especially in cancer therapy. However, the in situ-triggered and efficient transport of CO to tumors are the primary obstacles that limit its clinical applicability. To address this obstacle, herein, a H2O2-triggered CO gas releasing nanoplatform has been designed by embedding manganese carbonyl (MnCO) into Zr (IV)-based metal-organic frameworks (MOFs). The porous structures of MOFs provide encapsulation capacity for glucose oxidase (GOx) loading, thereby catalyzing the endogenous glucose into gluconic acid and H2O2 to accelerate CO release and energy depletion. In the meantime, the Mn2+ produced by MnCO can react with intracellular H2O2 via the Fenton reaction to form cytotoxic •OH. Therefore, the synthesized gas nanogenerator demonstrated a synergistic efficacy of CO gas therapy, reactive oxygen species (ROS)-mediated therapy, and energy starvation to prevent tumor growth. Both in vitro and in vivo studies indicated that this multifunctional nanoplatform not only successfully inhibited tumors through a synergistic effect, but also provided a new technique for the creation of starvation/gas/chemodynamic combination therapy in a single material. STATEMENT OF SIGNIFICANCE: In this study, we developed a H2O2 responsive CO gas nanogenerator to augment the in-situ generation of CO gas for combined modality therapy of tumors. The nanogenerator was constructed by encapsulating glucose oxidase (GOx) and manganese carbonyl (MnCO) into UiO-67-bpy, which can catalyze the conversion of intracellular glucose to H2O2 for cutting off energy supply of cancer cells. Meanwhile, the cumulated H2O2 can trigger the release of CO for gas therapy and generation of •OH for chemodynamic therapy (CDT) via the Fenton-like reaction, thereby resulting in apoptosis of the cancer cells. Collectively, our designed nanotherapeutic agent not only displays the synergistic therapy efficacy of starvation-enhanced CO gas therapy and CDT, but also provides an efficient strategy for developing the intelligent nanocarrier for CO gas delivery and release.