Size, Shape, and Sequence-Dependent Immunogenicity of RNA Nanoparticles.
Size, Shape, and Sequence-Dependent Immunogenicity of RNA Nanoparticles.
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DOI：
10.1016/j.omtn.2017.10.010
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发表时间：
2017-12-15
期刊：
影响因子：
--
通讯作者：
Guo P
中科院分区：
文献类型：
--
作者：
Guo S;Li H;Ma M;Fu J;Dong Y;Guo P
RNA分子已经成为一种很有前途的治疗方法。与所有其他药物一样，安全性和免疫反应是药物评价的重要标准。然而，关于RNA免疫原性的文献一直存在争议。在这里，我们使用RNA纳米技术的方法来证明RNA纳米颗粒的免疫反应是大小、形状和序列依赖的。采用形状相同但大小不同或大小相同但形状不同的RNA三角形、正方形、五边形和四面体作为研究免疫反应的模型。这些RNA纳米结构诱导的促炎细胞因子水平在巨噬细胞样细胞和动物中进行了评估。研究发现，顶点处无延伸的RNA多边形具有免疫惰性。然而，当具有特定序列的单链RNA从RNA多边形的顶点延伸时，检测到强烈的免疫反应。这些免疫刺激是序列特异性的，因为其他一些扩展序列很少或没有引起免疫反应。此外，RNA方阵尺寸越大，细胞因子分泌越强。三维RNA四面体比平面RNA三角形具有更强的免疫刺激作用。这些结果表明，RNA纳米颗粒的免疫原性是可调节的，既可以产生最小的免疫反应，作为安全的治疗载体，也可以产生强烈的免疫反应，用于癌症免疫治疗或疫苗佐剂。
RNA molecules have emerged as promising therapeutics. Like all other drugs, the safety profile and immune response are important criteria for drug evaluation. However, the literature on RNA immunogenicity has been controversial. Here, we used the approach of RNA nanotechnology to demonstrate that the immune response of RNA nanoparticles is size, shape, and sequence dependent. RNA triangle, square, pentagon, and tetrahedron with same shape but different sizes, or same size but different shapes were used as models to investigate the immune response. The levels of pro-inflammatory cytokines induced by these RNA nanoarchitectures were assessed in macrophage-like cells and animals. It was found that RNA polygons without extension at the vertexes were immune inert. However, when single-stranded RNA with a specific sequence was extended from the vertexes of RNA polygons, strong immune responses were detected. These immunostimulations are sequence specific, because some other extended sequences induced little or no immune response. Additionally, larger-size RNA square induced stronger cytokine secretion. 3D RNA tetrahedron showed stronger immunostimulation than planar RNA triangle. These results suggest that the immunogenicity of RNA nanoparticles is tunable to produce either a minimal immune response that can serve as safe therapeutic vectors, or a strong immune response for cancer immunotherapy or vaccine adjuvants.
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