Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA.
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China.
Small. 2017 Nov;13(43). doi: 10.1002/smll.201701432. Epub 2017 Jul 11.
Unwanted stimulation of the innate immune system by foreign nucleic acids has been one of the major barriers preventing bioactive sequences from reaching market. Foreign nucleic acids can be recognized by multiple pattern recognition receptors (PRRs), which trigger a signaling cascade to activate host defense systems, leading to a range of side effects. This study demonstrates that polyethylene glycol (PEG)-modified DNA strands can greatly reduce the activation of the innate immune system, and the extent of reduction is dependent upon polymer architecture. Highly branched brushes with long PEG side chains achieve the best suppression by blocking PRR interactions via a local steric effect. Interestingly, the brush polymer creates little barrier toward DNA-DNA interaction. Quantification of inflammatory cytokines in both mRNA and protein levels as well as the extent of cellular uptake shows a direct correlation between steric congestion and reduction of cellular immune response. These results suggest that the brush architecture offers unique advantages for PEGylating oligonucleotides in the context of minimizing unwanted immune system activation.
外源性核酸对固有免疫系统的非预期刺激一直是阻止生物活性序列进入市场的主要障碍之一。多种模式识别受体（PRR）可以识别外源性核酸，从而触发信号级联反应激活宿主防御系统，导致一系列副作用。本研究表明，聚乙二醇（PEG）修饰的 DNA 链可以大大降低固有免疫系统的激活，其降低程度取决于聚合物结构。具有长 PEG 侧链的高度支化刷状聚合物通过空间位阻效应阻断 PRR 相互作用，从而达到最佳抑制效果。有趣的是，刷状聚合物对 DNA-DNA 相互作用几乎没有阻碍。通过 mRNA 和蛋白质水平的炎症细胞因子定量以及细胞摄取程度，表明空间拥挤与细胞免疫反应的降低之间存在直接相关性。这些结果表明，在最小化不必要的免疫系统激活的情况下，刷状结构为聚乙二醇化寡核苷酸提供了独特的优势。
