Functional Nanoparticles Of Glucose Oxidase For Enhanced Cancer Immunotherap

Cancer has now become a highly prevalent global public health issue,posing a serious threat to human life and well-being.Immunotherapy is an emerging cancer treatment approach that utilizes a patient’s own immune system to kill cancer cells.Not only does it have good therapeutic effects,but it also has fewer side effects,making it a research hotspot in cancer treatment.However,due to the limitations of poor tumor immunogenicity and immune escape,the clinical efficacy of immunotherapy remains limited.In this paper,we designed a series of functional nanoscale glucose oxidase enzymes to enhance the immune response through a"source control and flow restriction"approach.On one hand,"source control"involves the use of small-sized gold nanoparticles（AuNP）to replace natural glucose oxidase（GOx）,overcoming the shortcomings of GOx’s short half-life,instability,and easy inactivation under biological conditions.At the same time,through near-infrared light（NIR）induced photothermal effect of gold nanorods（AuNR）,we can both enhance the catalytic efficiency of AuNP,accelerate glucose consumption,and achieve tumor starvation therapy,as well as suppress the expression of heat shock proteins（HSP）,amplifying excessive heat within tumor cells,inducing tumor cell death,and enhancing immunogenicity.On the other hand,"flow restriction"involves the use of small molecule drugs to inhibit immune escape or the application of divalent metal ions to modulate immunity and activate T cells to amplify the immunotherapy effect.These two approaches work synergistically,significantly inhibiting tumor growth and providing new strategies for enhancing anti-tumor immunotherapy.The research in this paper is mainly divided into the following two parts:（1）We have designed a nanozyme with both catalase-like（CAT）activity and GOx-mimicking activity,which can achieve bidirectional enhancement of immunotherapy.This nanozyme is composed of an AuNR core coated with a CeO₂ shell,with small-sized AuNPs deposited on its surface,loaded with small molecule inhibitor JQ1,and finally wrapped in cancer cell membranes（AuNR@CeO₂/AuNP-JQ1@M）.When it reaches the tumor site through the homotypic adhesion function of the cancer cell membrane,the AuNR induces a temperature increase under NIR irradiation,enhancing the GOx-like activity of the AuNP.The hydrogen peroxide（H₂O₂）generated from glucose consumption reacts with CeO₂ in situ to produce oxygen（O₂）,achieving self-accelerated glucose consumption,while suppressing HSP expression,amplifying the excessive heat effect within cells,causing oxidative stress,activating cell pyroptosis-related proteins,inducing tumor cell pyroptosis,and enhancing immunogenicity.In addition,the loaded JQ1 downregulates the expression of PD-L1 on tumor cells,blocking the binding of PD-L1 to PD-1,inhibiting immune escape,and amplifying the immunotherapy effect.（2）In order to better disperse AuNP,enhance its catalytic activity,and achieve divalent metal ion-activated immunity,we designed a structure in which AuNR is encapsulated within a zeolitic imidazolate framework（ZIF）material,allowing for the uniform deposition of AuNP on its surface to obtain functional nanoglucosidase oxidase AuNR@ZIF/AuNP.When the nanoenzyme reaches tumor cells,AuNR induces a temperature increase under NIR irradiation,further enhancing the catalytic activity of AuNP,causing tumor"starvation"and leading to high-temperature-induced tumor cell death,thus enhancing immunogenicity.At the same time,ZIF undergoes self-degradation in the acidic lysosomes of tumor cells,releasing an excess of Zn²⁺and disrupting the zinc homeostasis in the tumor cells.Zn²⁺overload reduces membrane integrity,promoting anti-tumor immune responses by inducing reactive oxygen species（ROS）production and activating the cGas-STING signaling pathway in tumor cells,as well as inducing the expression of chemokines CXCL9/10/11 and the phosphorylation of cytoplasmic protein tyrosine kinase（ZAP-70）,ultimately activating T cells and enhancing their recruitment.