Polymer-derived biomaterials for mRNA delivery to induce antigen-specific immune tolerance

项目摘要 免疫系统保护人们免受病原体的侵袭。然而，它有时会产生异常的免疫力。 对无害的环境抗原或患者自身抗原的反应，导致过敏或自身免疫 疾病，分别。这些过敏症影响着数百万美国人，并危及美国人的生命。 严酷的条件。目前的治疗策略通常需要终生治疗和/或广泛的 免疫抑制，造成不良反应。诱导抗原特异性免疫耐受是一种很有前途的方法。 在不影响免疫保护的情况下治疗过敏症的策略，因为该策略 特别是清除与疾病相关的免疫细胞或抑制它们的过敏反应，留下 免疫系统完好无损。这种宽容一旦确立，可能会持续终生。尽管在以下方面取得了进展 在这一领域，诱导有效的抗原特异性免疫耐受的技术仍有待开发。钥匙 成功的耐受诱导是靶向免疫细胞的精确调控。与小剂量药物相比 分子，一组从免疫细胞中传递的信使RNA(MRNAs)翻译而来的蛋白质可以发挥作用 以更精确的方式转换单元格。新冠肺炎基因疫苗的成功 验证了信使核糖核酸作为抗原特异性免疫刺激的平台。然而，mRNA的传递对于 诱导免疫耐受与免疫刺激的作用相反，目前还没有建立起来。这是因为 大多数报道的信使核糖核酸纳米载体会引起炎症反应和/或不能靶向正确的抗原- 提呈细胞(APC)启动耐受诱导过程。我们最近展示了我们的聚合物 纳米颗粒可以有效靶向肝窦内皮细胞，而肝窦内皮细胞是一种天然的APC 帮助免疫系统保持耐受性。我们假设纳米载体是从这种聚合物衍生出来的 纳米颗粒可以将抗原和编码耐受蛋白的mRNAs共同递送到LSECs，诱导抗原- 特异性免疫耐受性。在我们的初步研究中，我们证明了这样的纳米载体可以传递mrna。 全身性给药后，在小鼠体内进行蛋白质翻译。我们还证明了纳米载体 负载抗原可以抑制抗原特异性T细胞在体内治疗后的重新刺激 老鼠。我们将通过1)评估各种包裹抗原和纳米载体的配方来检验我们的假设 2)研究所选纳米载体在体内的生物分布及其耐受性； 3)在动物疾病模型中验证纳米载体的有效性，并阐明其作用机制。我们的建议 这项研究有望通过mrna实现抗原特异性耐受，从而产生广泛的科学和社会影响。 送货。

Project Summary The immune system protects people from pathogens. However, it sometimes generates abnormal immune reactions against harmless environmental antigens or patient’s own antigens, leading to allergy or autoimmune diseases, respectively. These hypersensitivity disorders affect millions of Americans and are life-threatening in severe conditions. Current therapeutic strategies often require lifelong treatment and/or broad immunosuppression, causing adverse effects. The induction of antigen-specific immune tolerance is a promising strategy to treat hypersensitivity without compromising immune protection because this strategy either specifically eliminate the disease-related immune cells or restrains their hypersensitive response, leaving the immune system intact. The tolerance may last lifelong once established. Although progress has been made in this area, technologies that induce efficient antigen-specific immune tolerance remain to be developed. The key to success in tolerance induction is the precise modulation of targeted immune cells. Compared to small drug molecules, a set of proteins translated from delivered messenger RNAs (mRNAs) in immune cells can work coordinately to transform the cells in a more precise manner. The success of COVID-19 mRNA vaccines has validated mRNA delivery as a platform for antigen-specific immune stimulation. However, mRNA delivery for inducing immune tolerance, an opposite effect as immune stimulation, has not been established. This is because most reported mRNA delivery nanocarriers cause inflammatory response and/or cannot target the right antigen- presenting cells (APCs) to initiate the process of tolerance induction. We have recently shown that our polymeric nanoparticle could efficiently target liver sinusoidal endothelial cells (LSECs), which are a type of APCs naturally helping the immune system maintain tolerance. We hypothesize that nanocarriers derived from this polymeric nanoparticle can co-deliver antigens and mRNAs encoding tolerogenic proteins to LSECs to induce antigen- specific immune tolerance. In our preliminary study, we demonstrated that such a nanocarrier can deliver mRNA to LSECs in mice for protein translation after systemic administration. We also demonstrated that the nanocarrier loaded with an antigen can inhibit the antigen-specific T cells from being restimulated after in vivo treatment of mice. We will test our hypothesis by 1) evaluating diverse nanocarrier formulations encapsulating antigen and mRNA in vitro; 2) investigating the biodistribution of selected nanocarriers and their tolerogenic potential in vivo; 3) demonstrating nanocarrier efficacy in animal disease models and elucidating the mechanism. Our proposed study is expected to have a broad scientific and societal impact by achieving antigen-specific tolerance via mRNA delivery.