Delivery of siRNAs to Dendritic Cells Using DEC205-Targeted Lipid Nanoparticles to Inhibit Immune Responses.
Delivery of siRNAs to Dendritic Cells Using DEC205-Targeted Lipid Nanoparticles to Inhibit Immune Responses.
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DOI：
10.1038/mt.2015.175
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Palliser D
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文献类型：
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作者：
Katakowski JA;Mukherjee G;Wilner SE;Maier KE;Harrison MT;DiLorenzo TP;Levy M;Palliser D
由于 siRNA 能够抑制任何基因的表达，因此它被誉为治疗多种疾病的理想候选药物，包括那些涉及“不可成药”靶标的疾病。然而，由于缺乏有效的递送载体，siRNA 的治疗潜力仍然受到严重限制。最近，含有可电离阳离子脂质的脂质纳米颗粒（LNP）已被开发用于肝脏 siRNA 递送。然而，它们是否适合递送至其他细胞类型尚未确定。我们修改了 LNP，以优先靶向树突状细胞 (DC)，即免疫反应的中央调节因子。为了实现定向递送，我们用针对小鼠 DEC205 的单链抗体（scFv；DEC-LNP）包被 LNP，该抗体在不同的 DC 亚群上高度表达。在这里，我们表明，封装在 DEC-LNP 中的 siRNA 的注射优先递送至 DEC205+ DC。摄取含有针对共刺激分子 CD40、CD80 和 CD86 特异的 siRNA 的 DEC-LNP 后，基因敲除会显着降低基因表达水平。我们通过混合淋巴细胞反应（MLR）证明了这种敲低的功能。总的来说，我们报告说，注射经过修饰的 LNP 以限制其对不同细胞群的吸收，可以产生深度基因敲低，足以抑制 MLR 等强大的免疫反应。
Due to their ability to knock down the expression of any gene, siRNAs have been heralded as ideal candidates for treating a wide variety of diseases, including those involving “undruggable” targets. However, the therapeutic potential of siRNAs remains severely limited by a lack of effective delivery vehicles. Recently, lipid nanoparticles (LNPs) containing ionizable cationic lipids have been developed for hepatic siRNA delivery. However, their suitability for delivery to other cell types has not been determined. We have modified LNPs for preferential targeting to dendritic cells (DCs), central regulators of immune responses. To achieve directed delivery, we coated LNPs with a single-chain antibody (scFv; DEC-LNPs), specific to murine DEC205, which is highly expressed on distinct DC subsets. Here we show that injection of siRNAs encapsulated in DEC-LNPs are preferentially delivered to DEC205+ DCs. Gene knockdown following uptake of DEC-LNPs containing siRNAs specific for the costimulatory molecules CD40, CD80, and CD86 dramatically decreases gene expression levels. We demonstrate the functionality of this knockdown with a mixed lymphocyte response (MLR). Overall, we report that injection of LNPs modified to restrict their uptake to a distinct cell population can confer profound gene knockdown, sufficient to inhibit powerful immune responses like the MLR.