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Immunomodulation through Nanocapsule-Mediated Cytosolic Delivery of siRNA

Immunomodulation through Nanocapsule-Mediated Cytosolic Delivery of siRNA
通过纳米胶囊介导的 siRNA 胞质传递进行免疫调节
批准号:
9315412
负责人:
VINCENT M. ROTELLO
金额:
$19.05万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-02-15 至 2019-01-31

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中文摘要
翻译
项目摘要/摘要 纳米胶囊介导的胞浆递送的免疫调节作用 小干扰RNA RNA干扰是一种潜在的强大的免疫治疗策略。一个关键的障碍 这种方法的缺点是不能有效地将siRNA传递到细胞质:目前 策略绝大多数siRNA仍然被困在内体中,是无效的。 纳米颗粒稳定的胶囊(NPSCs)将siRNA直接输送到胞浆中 膜融合过程,绕过内吞作用。我们已经证明了我们的有效性 在体外和体内在脾中都被击倒,后者需要显著 比目前的给药策略更低的剂量。在我们提议的研究中,我们将在 体外和体内实验优化这些化合物的免疫调节特性 载体,重点是通过靶向细胞因子肿瘤坏死因子-α来减少炎症反应。 我们提出的计划有两个目标: 目标1:我们将构建和优化基于siRNA的治疗性NPSCs,重点是 最大化胞浆递送效率、载体容量和肿瘤坏死因子-α基因敲除 对巨噬细胞的作用,同时将毒性和非特异性免疫反应降至最低。 目标2:我们将确定我们的递送系统对内毒素- 细菌性脓毒症小鼠模型的成像和抗感染效果评价 携带siRNA的NPSC治疗后的炎症效应。 本提案的目标是展示NPSC平台对 免疫调节。我们将建立在高效的siRNA胞浆递送的基础上 在我们的初步NPSC结果中观察,在体内评估和优化其 行为。这些研究将为这本书的翻译潜力提供关键的见解 载体,为在特定免疫中的应用提供了必要的初步结果 精神错乱。
英文摘要
Project Summary/Abstract Immunomodulation through Nanocapsule-Mediated Cytosolic Delivery of siRNA RNA interference is a potentially powerful strategy for immunotherapy. A key barrier to this approach is the inability to effectively deliver siRNA to the cytosol: with current strategies the vast majority of siRNA remains trapped in endosomes and is ineffective. Nanoparticle-stabilized capsules (NPSCs) deliver siRNA directly to the cytosol in a membrane fusion-like process, bypassing endocytosis. We have demonstrated effective knockdown both in vitro and in vivo in the spleen, with the latter requiring significantly lower dosing than current delivery strategies. In our proposed research we will use in vitro and in vivo experiments to optimize the immunomodulatory properties of these vehicles, focusing on reducing inflammatory response by targeting the cytokine TNF-α. Our proposed program features two Aims: Aim 1: We will fabricate and optimize therapeutic siRNA-based NPSCs, focusing on maximizing cytosolar delivery efficiency, carrier capacity, and TNF-α knockdown to macrophages while minimizing toxicity and non-specific immune response. Aim 2: We will determine the efficacy of our delivery system in lipopolysaccharide- challenged mouse models of bacterial sepsis, via imaging and evaluation of anti- inflammatory effects following siRNA-bearing NPSC treatment. The goal of this proposal is to demonstrate the utility of the NPSC platform for immunomodulation. We will build upon the highly efficient cytosolar delivery of siRNA observed in our preliminary NPSC results, evaluating and optimizing their in vivo behavior. These studies will provide critical insights to the translational potential of this vehicle, providing essential preliminary results for applications in specific immune disorders.
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