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Viral Protein-Pseudotyped and siRNA-Electroporated Extracellular Vesicles for Cancer Immunotherapy

机译：病毒蛋白 - 假型和siRNA电穿孔的癌症免疫治疗细胞外囊泡

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摘要

Extracellular vesicles (EVs) have shown great potential in drug delivery, disease diagnosis, and treatment owing to their versatile native features and functions. RNA interference (RNAi) therapeutics that block the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway have attracted increasing interest for the treatment of various cancers. Here, immunoregulatory EVs are developed by decorating M1-macrophage-derived EVs (M1 EV) with vesicular stomatitis virus glycoprotein (VSV-G), a pH-responsive viral fusion protein, and electroporating anti-PD-L1 siRNA (siPD-L1) into the EVs. After administration to CT26 tumor-bearing mice, this virus-mimic nucleic acid engineered EVs (siRNA@V-M1 EV) can target tumor tissues, which is attributed to the natural tumor-homing property of M1 EV. Then, the fusion of VSV-G with cells facilitates the direct release of siPD-L1 into the cytoplasm and triggers robust gene silencing, leading to the efficient block of PD-L1/PD-1 interaction and then the elevation of CD8(+)T cell population. Meanwhile, the M1 EVs and IFN-gamma secreted by the CD8(+)T cells promote the repolarization of M2 tumor-associated macrophages to M1 macrophages. The combination of PD-L1/PD-1 pathway blocking, T cell recognition reconstructing, and M1 macrophage repolarization via multifunctional EVs can achieve satisfactory antitumor efficacy in this tumor model, showing potential as a new modality to fight cancers.
机译：由于其多功能的天然特征和功能，细胞外囊（EVS）表现出巨大的药物递送，疾病诊断和治疗潜力。阻断程序死亡-1（PD-1）和编程死亡 - 配体1（PD-L1）途径的RNA干扰（RNAi）治疗剂吸引了对各种癌症治疗的兴趣越来越令人感兴趣。这里，通过用囊泡口炎病毒糖蛋白（VSV-G），pH-响应病毒融合蛋白和电穿孔抗PD-L1 siRNA（SIPD-L1）来开发免疫调节EVS。进入EVS。在给CT26肿瘤的小鼠施用后，该病毒模拟核酸工程EVS（siRNA @ V-M1eV）可以靶向肿瘤组织，其归因于M1eV的天然肿瘤归巢性能。然后，使用细胞的VSV-g融合促进SIPD-L1进入细胞质的直接释放，并触发鲁棒基因沉默，导致PD-L1 / PD-1相互作用的有效块，然后是CD8（+）的升高T细胞群体。同时，CD8（+）T细胞分泌的M1 EVS和IFN-GAMMA促进了M2肿瘤相关巨噬细胞对M1巨噬细胞的再溶解。 PD-L1 / PD-1途径阻断，T细胞识别重建和M1通过多功能EVS的组合可以在该肿瘤模型中实现令人满意的抗肿瘤功效，显示出作为对抗癌症的新态度的潜力。

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  • 来源
    《Advanced Functional Materials》 |2020年第52期|2006515.1-2006515.11|共11页
  • 作者

    Liu Houli; Huang Lili; Mao Mingchuan; Ding Jingjing; Wu Guanghao; Fan Wenlin; Yang Tongren; Zhang Mengjie; Huang Yuanyu; Xie Hai-Yan;

  • 作者单位

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

    Beijing Inst Technol Sch Life Sci Adv Res Inst Multidisciplinary Sci Beijing 100081 Peoples R China;

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  • 正文语种 eng
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  • 关键词

    cancer immunotherapy; extracellular vesicles; M1 macrophages; siRNA; vesicular stomatitis virus glycoprotein;

    机译：癌症免疫疗法;细胞外囊;M1巨噬细胞;siRNA;囊泡口腔炎病毒糖蛋白;

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