Chao Qi

Abstract Chemodynamic therapy (CDT) is an emerging therapy method that kills cancer cells by converting intracellular hydrogen peroxide (H 2 O 2 ) into highly toxic hydroxyl radicals ( • OH). To overcome the current limitations of the insufficient endogenous H 2 O 2 and the high concentration of glutathione (GSH) in tumor cells, an intelligent nanocatalytic theranostics (denoted as PGC‐DOX) that possesses both H 2 O 2 self‐supply and GSH‐elimination properties for efficient cancer therapy is presented. This nanoplatform is constructed by a facile one‐step biomineralization method using poly(ethylene glycol)‐modified glucose oxidase (GOx) as a template to form biodegradable copper‐doped calcium phosphate nanoparticles, followed by the loading of doxorubicin (DOX). As an enzyme catalyst, GOx can effectively catalyze intracellular glucose to generate H 2 O 2 , which not only starves the tumor cells, but also supplies H 2 O 2 for subsequent Fenton‐like reaction. Meanwhile, the redox reaction between the released Cu 2+ ions and intracellular GSH will induce GSH depletion and reduce Cu 2+ to Fenton agent Cu + ions, and then trigger the H 2 O 2 to generate • OH by a Cu + ‐mediated Fenton‐like reaction, resulting in enhanced CDT efficacy. The integration of GOx‐mediated starvation therapy, H 2 O 2 self‐supply and GSH‐elimination enhanced CDT, and DOX‐induced chemotherapy, endow the PGC‐DOX with effective tumor growth inhibition with minimal side effects in vivo.

Glucose oxidase (GOx) is an endogenous oxido-reductase that is widely distributed in living organisms. Over recent years, GOx has attracted increasing interest in the biomedical field due to its inherent biocompatibility, non-toxicity, and unique catalysis against β-d-glucose. GOx efficiently catalyzes the oxidization of glucose into gluconic acid and hydrogen peroxide (H2O2), which can be employed by various biosensors for the detection of cancer biomarkers. Various cancer therapeutic strategies have also been developed based on the catalytic chemistry of GOx: (1) the consumption of glucose provides an alternative strategy for cancer-starvation therapy; (2) the consumption of oxygen increases tumor hypoxia, which can be harnessed for hypoxia-activated therapy; (3) the generation of gluconic acid enhances the acidity of the tumor microenvironment, which can trigger pH-responsive drug release; (4) the generation of H2O2 increases the levels of tumor oxidative stress, and the H2O2 can be converted into toxic hydroxyl radicals that can kill cancer cells upon exposure to light irradiation or via the Fenton reaction. More importantly, GOx can be combined with other enzymes, hypoxia-activated prodrugs, photosensitizers or Fenton's reagents, to generate multi-modal synergistic cancer therapies based on cancer starvation therapy, hypoxia-activated therapy, oxidation therapy, photodynamic therapy, and/or photothermal therapy. Such multi-modal approaches are anticipated to exert a stronger therapeutic effect than one therapeutic mode alone. Thus, maximizing the potential of GOx in a biomedical context will offer novel clinical solutions to diagnose and treat cancer. In this tutorial review, we introduce the recent advances of GOx in cancer diagnosis and treatment. We then emphasize the design principles and biomedical applications of GOx-based biosensors and cancer therapeutic approaches. Finally, we discuss the challenges and future prospects of GOx-based catalytic systems in biomedicine.

Over the past 3 years, glucose oxidase (GOx) has aroused great research interest in the context of cancer treatment due to its inherent biocompatibility and biodegradability, and its unique catalytic properties against β-d-glucose. GOx can effectively catalyze the oxidation of glucose into gluconic acid and hydrogen peroxide. This process depletes oxygen levels, resulting in elevated acidity, hypoxia, and oxidative stress in the tumor microenvironment. All of these changes can be readily harnessed to develop a multimodal synergistic cancer therapy by combining GOx with other therapeutic approaches. Herein, the representative studies of GOx-instructed multimodal synergistic cancer therapy are introduced, and their synergistic mechanisms are discussed systematically. The current challenges and future prospects to advance the development of GOx-based nanomedicines in this cutting-edge research area are highlighted.

Glucose oxidase (GOx) has been recognized as a “star” enzyme catalyst involved in cancer treatment in the past few years. Herein, GOx is mineralized with manganese-doped calcium phosphate (MnCaP) to form spherical nanoparticles (GOx-MnCaP NPs) by an in situ biomimetic mineralization method, followed by the loading of doxorubicin (DOX) to construct a biodegradable, biocompatible, and tumor acidity-responsive nanotheranostics for magnetic resonance imaging (MRI) and cascade reaction-enhanced cooperative cancer treatment. The GOx-driven oxidation reaction can effectively eliminate intratumoral glucose for starvation therapy, and the elevated H2O2 is then converted into highly toxic hydroxyl radicals via a Mn2+-mediated Fenton-like reaction for chemodynamic therapy (CDT). Moreover, the acidity amplification due to the gluconic acid generation will in turn accelerate the degradation of the nanoplatform and promote the Mn2+–H2O2 reaction for enhanced CDT. Meanwhile, the released Mn2+ ions can be used for MRI to monitor the treatment process. After carrying the anticancer drug, the DOX-loaded GOx-MnCaP can integrate starvation therapy, Mn2+-mediated CDT, and DOX-induced chemotherapy together, which showed greatly improved therapeutic efficacy than each monotherapy. Such an orchestrated cooperative cancer therapy demonstrated high-efficiency tumor suppression on 4T1 tumor-bearing mice with minimal side effects. Our findings suggested that the DOX-loaded GOx-MnCaP nanotheranostics with excellent biodegradability and biocompatibility hold clinical translation potential for cancer management.

Abstract As an essential micronutrient, manganese (Mn) participates in various physiological processes and plays important roles in host immune system, hematopoiesis, endocrine function, and oxidative stress regulation. Mn‐based nanoparticles are considered to be biocompatible and show versatile applications in nanomedicine, in particular utilized in tumor immunotherapy in the following ways: 1) acting as a biocompatible nanocarrier to deliver immunotherapeutic agents for tumor immunotherapy; 2) serving as an adjuvant to regulate tumor immune microenvironment and enhance immunotherapy; 3) activating host's immune system through the cGAS‐STING pathway to trigger tumor immunotherapy; 4) real‐time monitoring tumor immunotherapy effect by magnetic resonance imaging (MRI) since Mn 2+ ions are ideal MRI contrast agent which can significantly enhance the T 1 ‐weighted MRI signal after binding to proteins. This comprehensive review focuses on the most recent progress of Mn‐based nanoplatforms in tumor immunotherapy. The characteristics of Mn are first discussed to guide the design of Mn‐based multifunctional nanoplatforms. Then the biomedical applications of Mn‐based nanoplatforms, including immunotherapy alone, immunotherapy‐involved multimodal synergistic therapy, and imaging‐guided immunotherapy are discussed in detail. Finally, the challenges and future developments of Mn‐based tumor immunotherapy are highlighted.