Ren Hao, Bai Yunhao, Liu Zhangya, Ma Chenyu, Tao Xinyue, Wang Qiyue, Lian Huibo, Li Xueming
School of Pharmaceutical Science, Nanjing Tech University, Nanjing, Jiangsu 211816, China.
School of Pharmaceutical Science, Nanjing Tech University, Nanjing, Jiangsu 211816, China.
Acta Biomater. 2024 Dec;190:501-517. doi: 10.1016/j.actbio.2024.11.004. Epub 2024 Nov 7.
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 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 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 coating exposes the GOx enzyme, thereby initiating a cascade catalysis reaction to generate hydrogen peroxide (HO) and release CO in the hypoxic conditions. Additionally, the released Mn reacts with HO 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 MnO gatekeeper was developed to perform synergistic treatments involving starvation therapy, CO gas therapy and chemodynamic therapy (CDT) for tumor elimination. The MnO 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.
葡萄糖氧化酶（GOx）介导的饥饿疗法是一种有效的肿瘤治疗方法，它能阻断能量供应并激活免疫反应。然而，肿瘤免疫原性不足和免疫抑制性肿瘤微环境（TME）限制了其治疗效果。为了解决这一问题，我们设计了一种带有MnO涂层的多功能级联气体纳米反应器，该涂层作为外部门卫，用于封装GOx和一氧化碳（CO）供体（称为GCM）。由于MnO涂层的保护作用，GCM在正常生理环境中保持更好的稳定性，增强了GOx的催化活性并将毒副作用降至最低。在肿瘤中积聚后，MnO涂层的降解使GOx酶暴露，从而引发级联催化反应，在缺氧条件下产生过氧化氢（HO）并释放CO。此外，释放出的Mn与HO反应生成有毒的羟基自由基（•OH），作为化学动力疗法（CDT）。饥饿疗法、CO气体疗法和CDT的协同治疗有效地杀死癌细胞并放大免疫原性细胞死亡（ICD），使树突状细胞成熟并激活抗肿瘤免疫反应。此外，释放出的CO增加了M1巨噬细胞的浸润并减少了髓源性抑制细胞（MDSC）的浸润，从而逆转了免疫抑制性TME。这种多功能气体纳米反应器为产生CO气体以触发强大的抗肿瘤免疫反应提供了一种策略，并且在癌症免疫治疗中具有临床应用潜力。重要意义声明：开发了一种带有MnO门卫的多功能级联气体纳米反应器，用于进行涉及饥饿疗法、CO气体疗法和化学动力疗法（CDT）的协同治疗以消除肿瘤。MnO门卫通过产生氧气增强了纳米反应器内GOx的催化活性，从而将静脉注射后的毒副作用降至最低。气体纳米反应器通过协同治疗放大ICD，使树突状细胞成熟并激活抗肿瘤免疫反应。此外，释放出的CO可以逆转TME的免疫抑制作用以增强癌症免疫治疗。利用气体纳米反应器的联合策略显示出促进癌症免疫治疗的临床潜力。
