IDO blockade-based immunotherapy has been impeded by the activation of antitumor immune response and low delivery efficiency of immunotherapeutic, resulting from natural biological barriers and immune resistance. Herein, a programmable drug delivery nanosystem with enhanced tumor penetration and endocytosis is constructed for chemotherapy-enhanced immunotherapy by loading immune checkpoint IDO inhibitor NLG919 in pH/redox cascade-responsive prodrug micelle. The nanosystem shrinked micelles sizes and converted charge from negative to positive for enhanced tumor penetration and endocytosis in responding to the weakly acidic tumor microenvironment. The endocytosed nanosystem dramatically disassembled and released curcumin and NLG919 in redox-rich cytoplasm. In vitro and in vivo studies demonstrate that the nanosystem not only effectively overcame biological barriers, but also significantly boosted antitumor immune response and reduced immune resistance. It was realized by the combined effects of chemotherapy-enhanced immunogenicity, and NLG919-induced IDO-blockade immunotherapy, consequently inhibiting tumor growth, metastasis and recurrence with high efficiency in vivo. The study offers a nanoplatform with deep tumor penetration, high cellular uptake and effective antitumor immune response for the advance of chemo-immunotherapy.

中文翻译：

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可编程前药胶束，具有尺寸缩小和电荷反转的特性，可用于化学疗法改进的IDO免疫疗法。

由于天然生物屏障和免疫抗性的原因，抗肿瘤免疫应答的激活和免疫治疗的低递送效率已阻碍了基于IDO阻断的免疫治疗。本文中，通过将免疫检查点IDO抑制剂NLG919装入pH /氧化还原级联反应前药胶束中，构建了具有增强的肿瘤渗透性和内吞作用的可编程药物输送纳米系统，以用于化学疗法增强的免疫治疗。纳米系统缩小了胶束的大小，并将电荷从负电荷转换为正电荷，从而增强了对弱酸性肿瘤微环境的肿瘤渗透和内吞作用。被内吞的纳米系统在富含氧化还原的细胞质中急剧分解并释放姜黄素和NLG919。体外和体内研究表明，纳米系统不仅有效地克服了生物屏障，而且还显着增强了抗肿瘤免疫反应并降低了免疫抵抗力。它是通过化学疗法增强的免疫原性和NLG919诱导的IDO阻断免疫疗法的联合作用实现的，从而在体内高效抑制肿瘤的生长，转移和复发。这项研究提供了一种具有深层肿瘤渗透性，高细胞摄取率和有效抗肿瘤免疫应答的纳米平台，以促进化学免疫疗法的发展。体内高效转移和复发。这项研究提供了一种具有深层肿瘤渗透性，高细胞摄取率和有效抗肿瘤免疫应答的纳米平台，以促进化学免疫疗法的发展。体内高效转移和复发。这项研究提供了一种具有深层肿瘤渗透性，高细胞摄取率和有效抗肿瘤免疫应答的纳米平台，以促进化学免疫疗法的发展。