Polymersome Nanoreactor-Mediated Combination Chemodynamic-Immunotherapy via ROS Production and Enhanced STING Activation,Advanced Therapeutics

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Polymersome Nanoreactor-Mediated Combination Chemodynamic-Immunotherapy via ROS Production and Enhanced STING Activation
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2021-09-07 , DOI: 10.1002/adtp.202100130
Qinghao Zhou ₁ , Yuheng Wang ₁ , Xiang Li ₁ , Nannan Lu ₂ , Zhishen Ge ₁

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Stimulator of interferon genes (STING) activation by STING agonists has been recognized as one of important immunotherapy strategies. However, immunosuppressive tumor microenvironment always hinders the therapeutic efficacy of cancer immunotherapy. Herein, ferrocene-containing polymersome nanoreactors are engineered by co-loading glucose oxidase (GOD) and STING agonist, symmetry-linked amidobenzimidazole (DiABZI), for enhanced STING activation and combination chemodynamic-immunotherapy. After intravenous injection, the polymersomes can accumulate in tumor tissues. The tumor acidity-triggered polymersome membrane permeability allows the entrance of tumoral glucose and oxygen for H₂O₂ production by GOD, which is further transformed into hydroxyl radicals (•OH) under the catalysis of ferrocene moieties. Chemodynamic therapy (CDT) based on •OH can induce efficient cellular apoptosis and release of fragmented DNA and tumor-associated antigens to promote endogenous STING activation and reverse immunosuppressive tumor microenvironment. Simultaneously, pH-responsive release of DiABZI activates STING pathway to elicit antitumor immune responses. Therefore, DiABZI and CDT synergistically enhance the antitumor immunity via combination chemodynamic-immunotherapy. The primary tumors are completely ablated and the growth of distant tumors that are established after treatment is also suppressed efficiently. The polymersome nanoreactor-mediated chemodynamic-immunotherapy represents a promising treatment strategy toward primary solid and metastatic tumors.

中文翻译：

聚合体纳米反应器介导的联合化学动力学-免疫疗法通过 ROS 产生和增强的 STING 激活

STING 激动剂激活干扰素基因 (STING) 的刺激剂已被公认为重要的免疫治疗策略之一。然而，免疫抑制性肿瘤微环境总是阻碍癌症免疫疗法的治疗效果。在此，含二茂铁的聚合物囊泡纳米反应器通过共加载葡萄糖氧化酶 (GOD) 和 STING 激动剂、对称连接的酰胺基苯并咪唑 (DiABZI) 进行设计，以增强 STING 激活和组合化学动力学免疫疗法。静脉注射后，聚合物囊泡可在肿瘤组织中积聚。肿瘤酸度触发的聚合物体膜渗透性允许肿瘤葡萄糖和氧气进入 H ₂ O ₂由 GOD 产生，在二茂铁部分的催化下进一步转化为羟基自由基 (•OH)。基于•OH 的化学动力学疗法(CDT) 可诱导有效的细胞凋亡和碎片DNA 和肿瘤相关抗原的释放，以促进内源性STING 激活和逆转免疫抑制肿瘤微环境。同时，DiABZI 的 pH 响应性释放激活 STING 通路以引发抗肿瘤免疫反应。因此，DiABZI 和 CDT 通过联合化学动力学-免疫疗法协同增强抗肿瘤免疫。原发肿瘤完全消融，治疗后形成的远处肿瘤的生长也得到有效抑制。

更新日期：2021-09-07

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