Rationale: Vascular abnormality stemming from the hypoxia-driven elevation of proangiogenic factors is a hallmark for many solid malignant tumors, including colorectal cancer (CRC) and its liver metastasis. We report a hypoxia-triggered liposome-supported metal-polyphenol-gene bio-nanoreactor to tune the proangiogenic factor-mediated immunotolerance and synergize the elicited tumoricidal immunity for CRC treatment./nMethods: With the aid of polyphenol gallic acid, Cu²⁺ ion-based intracellular bio-nanoreactor was synthesized for the delivery of small interfering RNA targeting vascular endothelial growth factor and then cloaked with a hybrid liposomal membrane that harbored a hypoxia-responsive azobenzene derivative. In hypoxic tumor, the liposomal shell disintegrated, and a shrunk-size bio-nanoreactor was burst released. Intracellularly, Cu²⁺ from the bio-nanoreactor catalyzed a Fenton-like reaction with glutathione, which efficiently converted H₂O₂ to •OH and enabled a chemodynamic therapy (CDT) in tumor sites. With the alleviation of proangiogenic factor-mediated immunotolerance and high production of CDT-induced tumor-associated antigens, robust tumoricidal immunity was co-stimulated./nResults: With colorectal tumor and its liver metastasis models, we determined the underlying mechanism of proangiogenic factor-mediated immunotolerance and highlighted that the liposomal bio-nanoreactor could create positive feedback among the critical players in the vascular endothelium and synergize the elicited tumoricidal immunity./nConclusion: Our work provides an alternative strategy for exerting efficient tumoricidal immunity in the proangiogenic factor-upregulated subpopulation of CRC patients and may have a wide-ranging impact on cancer immune-anti-angiogenic complementary therapy in clinics.

中文翻译：

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原位调节促血管生成因子介导的免疫耐受通过缺氧可触发的脂质体生物纳米反应器协同发挥杀肿瘤免疫力。

理由：由缺氧引起的促血管生成因子升高引起的血管异常是许多实体恶性肿瘤的标志，包括结肠直肠癌（CRC）及其肝转移。我们报道了一个缺氧触发的脂质体支持的金属多酚基因生物纳米反应器，以调节促血管生成因子介导的免疫耐受并协同引起的CRC治疗肿瘤免疫性。/n方法：借助多酚没食子酸，Cu ²⁺合成基于离子的细胞内生物纳米反应器，以递送靶向血管内皮生长因子的小分子干扰RNA，然后用具有低氧反应性偶氮苯衍生物的杂化脂质体膜掩盖。在低氧性肿瘤中，脂质体壳崩解，并且缩小了尺寸的生物纳米反应器被释放。在细胞内，来自生物纳米反应器的Cu ²⁺催化与谷胱甘肽的Fenton样反应，从而有效地将H ₂ O ₂转化为•OH，并在肿瘤部位进行了化学动力学治疗（CDT）。随着促血管生成因子介导的免疫耐受的减轻和CDT诱导的肿瘤相关抗原的高产生，共刺激了强大的杀肿瘤免疫力。大肠癌肿瘤及其肝转移模型，我们确定的促血管生成因子介导的免疫耐受的发生机制，并强调指出，脂质体生物纳米反应器可在血管内皮创建关键球员之间的正反馈和增效引起的杀灭肿瘤immunity./n结论：我们的工作为在CRC患者促血管生成因子上调的亚群中发挥有效的肿瘤免疫力提供了另一种策略，并且可能在临床上对癌症免疫-抗血管生成辅助疗法产生广泛影响。