Hao Ren , Yunhao Bai , Zhangya Liu , Chenyu Ma , Xinyue Tao , Qiyue Wang , Huibo Lian , Xueming Li
{"title":"A multifunctional cascade gas-nanoreactor with MnO2 as a gatekeeper to enhance starvation therapy and provoke antitumor immune response","authors":"Hao Ren , Yunhao Bai , Zhangya Liu , Chenyu Ma , Xinyue Tao , Qiyue Wang , Huibo Lian , Xueming Li","doi":"10.1016/j.actbio.2024.11.004","DOIUrl":null,"url":null,"abstract":"<div><div>Glucose oxidase (GOx)-mediated starvation therapy is an effective tumor treatment that blocks energy and activates the immune response. However, the insufficient tumor immunogenicity and immunosuppressive tumor microenvironment (TME) limited its therapeutic efficacy. To address this, we have designed a multifunctional cascade gas-nanoreactor with a MnO<sub>2</sub> coating, which serves as an out gatekeeper to encapsulate both GOx and a carbon monoxide (CO) donor (denoted as GCM). Due to the protective effect of MnO<sub>2</sub> coating, GCM maintains better stability in normal physiological environments, enhancing the catalytic activity of GOx and minimizing toxic side effects. Upon accumulation in the tumor, the degradation of MnO<sub>2</sub> coating exposes the GOx enzyme, thereby initiating a cascade catalysis reaction to generate hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and release CO in the hypoxic conditions. Additionally, the released Mn<sup>2+</sup> reacts with H<sub>2</sub>O<sub>2</sub> to generate toxic hydroxyl radical (•OH) as chemodynamic therapy (CDT). The synergistic treatments of starvation therapy, CO gas therapy and CDT effectively kill cancer cells and amplify immunogenic cell death (ICD), maturing DC cells and activating anti-tumor immune response. Furthermore, the released CO increases M1 macrophages infiltration and reduces myeloid-derived suppressor cells (MDSCs) infiltration, thus reversing the immunosuppressive TME. This multifunctional gas-nanoreactor provides a strategy for CO gas generation to trigger a robust anti-tumor immune response and has the potential for clinical application in cancer immunotherapy.</div></div><div><h3>Statement of significance</h3><div>A multifunctional cascade gas-nanoreactor with a MnO<sub>2</sub> gatekeeper was developed to perform synergistic treatments involving starvation therapy, CO gas therapy and chemodynamic therapy (CDT) for tumor elimination. The MnO<sub>2</sub> gatekeeper enhanced the catalytic activity of GOx within the nanoreactor by generating oxygen, thereby minimizing toxic side effects after intravenous injection. The gas-nanoreactor amplified ICD through synergistic treatments to mature DC cells and activate anti-tumor immune response. Furthermore, the released CO could reverse the immunosuppression of the TME to enhance cancer immunotherapy. The combination strategy utilizing the gas-nanoreactor demonstrates clinical potential for facilitating cancer immunotherapy.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"190 ","pages":"Pages 501-517"},"PeriodicalIF":9.4000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Biomaterialia","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1742706124006585","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
引用次数: 0
Abstract
Glucose oxidase (GOx)-mediated starvation therapy is an effective tumor treatment that blocks energy and activates the immune response. However, the insufficient tumor immunogenicity and immunosuppressive tumor microenvironment (TME) limited its therapeutic efficacy. To address this, we have designed a multifunctional cascade gas-nanoreactor with a MnO2 coating, which serves as an out gatekeeper to encapsulate both GOx and a carbon monoxide (CO) donor (denoted as GCM). Due to the protective effect of MnO2 coating, GCM maintains better stability in normal physiological environments, enhancing the catalytic activity of GOx and minimizing toxic side effects. Upon accumulation in the tumor, the degradation of MnO2 coating exposes the GOx enzyme, thereby initiating a cascade catalysis reaction to generate hydrogen peroxide (H2O2) and release CO in the hypoxic conditions. Additionally, the released Mn2+ reacts with H2O2 to generate toxic hydroxyl radical (•OH) as chemodynamic therapy (CDT). The synergistic treatments of starvation therapy, CO gas therapy and CDT effectively kill cancer cells and amplify immunogenic cell death (ICD), maturing DC cells and activating anti-tumor immune response. Furthermore, the released CO increases M1 macrophages infiltration and reduces myeloid-derived suppressor cells (MDSCs) infiltration, thus reversing the immunosuppressive TME. This multifunctional gas-nanoreactor provides a strategy for CO gas generation to trigger a robust anti-tumor immune response and has the potential for clinical application in cancer immunotherapy.
Statement of significance
A multifunctional cascade gas-nanoreactor with a MnO2 gatekeeper was developed to perform synergistic treatments involving starvation therapy, CO gas therapy and chemodynamic therapy (CDT) for tumor elimination. The MnO2 gatekeeper enhanced the catalytic activity of GOx within the nanoreactor by generating oxygen, thereby minimizing toxic side effects after intravenous injection. The gas-nanoreactor amplified ICD through synergistic treatments to mature DC cells and activate anti-tumor immune response. Furthermore, the released CO could reverse the immunosuppression of the TME to enhance cancer immunotherapy. The combination strategy utilizing the gas-nanoreactor demonstrates clinical potential for facilitating cancer immunotherapy.
期刊介绍:
Acta Biomaterialia is a monthly peer-reviewed scientific journal published by Elsevier. The journal was established in January 2005. The editor-in-chief is W.R. Wagner (University of Pittsburgh). The journal covers research in biomaterials science, including the interrelationship of biomaterial structure and function from macroscale to nanoscale. Topical coverage includes biomedical and biocompatible materials.