Encapsulation of Glucose Oxidase in Porous Cu(II)-Doped Zinc Phosphate@polydopamine Nanoparticles for Triple-Combination Therapy of Cancer.

Designing multifunctional nanotherapeutic platforms that integrate multiple therapeutic capabilities with enhanced tumor specificity and low systemic toxicity has emerged as a promising strategy for cancer therapy. Herein, we put forward a simple and clear route to construct multifunctional nanoparticles (NPs) integrating chemodynamic therapy (CDT), starvation therapy (ST), and photothermal therapy (PTT) by using polydopamine as a protective layer to coat Cu2+-doped zinc phosphate loaded with glucose oxidase (designated as Cu-ZnP@GOx/PDA/PEG NPs) for optimizing therapeutic efficacy. The obtained Cu-ZnP@GOx/PDA/PEG NPs utilize porous Cu2+-doped ZnP to provide sufficient space for efficient GOx loading, while the PDA shell coated on the surface acts as a "gatekeeper" to prevent enzyme leakage and provides photothermal conversion capabilities. When Cu-ZnP@GOx/PDA/PEG NPs accumulate at tumor sites, the slightly acidic tumor microenvironment triggers the degradation of Cu-ZnP@GOx/PDA/PEG NPs, thereby releasing loaded GOx and doped Cu2+. The released Cu2+ is reduced to Cu+ by glutathione (GSH), subsequently catalyzing H2O2 decomposition to generate highly cytotoxic hydroxyl radicals (•OH) for effective CDT. The released GOx can cut off glucose metabolism in tumor cells to realize ST, and the substances produced during the process of glucose oxidation can improve the microenvironment for better CDT. Under near-infrared irradiation, the generated heat by the photothermal effect of PDA can not only be applied for PTT but also enhance the catalytic efficiency of Fenton-like reactions and the enzymatic activity of GOx, achieving the goal of trimodal synergistic therapy of CDT/ST/PTT. Importantly, in vivo studies using tumor-bearing mice demonstrate that the combined therapy via Cu-ZnP@GOx/PDA/PEG NPs effectively suppresses tumor growth, and no obvious systemic toxicity can be observed. Taken together, the construction of Cu-ZnP@GOx/PDA/PEG NPs can provide a feasible strategy for a safe and efficient cancer therapy.