Toll-Like Receptor-Mediated Recognition of Nucleic Acid Nanoparticles (NANPs) in Human Primary Blood Cells
Toll-Like Receptor-Mediated Recognition of Nucleic Acid Nanoparticles (NANPs) in Human Primary Blood Cells
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DOI：
10.3390/molecules24061094
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发表时间：
2019-03-02
期刊：
影响因子：
4.6
通讯作者：
Dobrovolskaia, Marina A.
中科院分区：
文献类型：
--
作者：
Hong, Enping;Halman, Justin R.;Dobrovolskaia, Marina A.
输注反应（IRs）为许多新疗法创造了转化障碍，包括那些利用纳米技术的疗法。核酸纳米粒子（NANPs）是一类新型的治疗药物，通过合理设计相对较短的寡核苷酸来自组装成各种可编程的几何形状。虽然细胞因子风暴（一种常见的IR）已经阻止了几种治疗性寡核苷酸的临床开发，但NANP技术具有巨大的潜力，可以通过调整颗粒的物理化学性质来控制这些反应，使其达到所需的免疫反应类型和强度。最近，我们首次全面研究了NANPs的形状、大小、组成及其在人细胞中的免疫识别之间的构效关系，并确定了吞噬酶体途径是NANPs摄取和随后免疫刺激的主要途径。在这里，我们探讨了NANPs被原代免疫细胞识别的分子机制，特别是toll样受体的作用。我们目前的研究扩大了对基于工程核酸的治疗方法的免疫识别的理解，并有助于改善纳米药物的安全性。
Infusion reactions (IRs) create a translational hurdle for many novel therapeutics, including those utilizing nanotechnology. Nucleic acid nanoparticles (NANPs) are a novel class of therapeutics prepared by rational design of relatively short oligonucleotides to self-assemble into various programmable geometric shapes. While cytokine storm, a common type of IR, has halted clinical development of several therapeutic oligonucleotides, NANP technologies hold tremendous potential to bring these reactions under control by tuning the particle's physicochemical properties to the desired type and magnitude of the immune response. Recently, we reported the very first comprehensive study of the structure-activity relationship between NANPs' shape, size, composition, and their immunorecognition in human cells, and identified the phagolysosomal pathway as the major route for the NANPs' uptake and subsequent immunostimulation. Here, we explore the molecular mechanism of NANPs' recognition by primary immune cells, and particularly the contributing role of the Toll-like receptors. Our current study expands the understanding of the immune recognition of engineered nucleic acid-based therapeutics and contributes to the improvement of the nanomedicine safety profile.