Polymeric Nanomaterials for Probing and Modulating Innate Immune Responses

摘要： 炎症是先天免疫系统针对任何外来入侵而触发的一种防御机制，以恢复 体内平衡，但当它持续数月至数年时，就会转变成慢性 导致多种有害疾病的状况。炎症小体是一种已知的异源多聚体蛋白质复合物 用于激活炎性半胱天冬酶，然后进行细胞因子的后续处理，这使其成为 炎症期间的关键角色。炎症小体的异常激活可能引发不良炎症 与慢性炎症性疾病进展相关的反应。多项研究调查了 纳米材料与免疫细胞的相互作用，以了解它们在各种生物应用中的作用并定制 他们满足不同的需求。事实上，几种类型的纳米材料已被广泛探索用于靶向免疫 疾病部位的细胞调节免疫反应。然而，我们最近的研究和最近的一些 报告表明，许多纳米材料非特异性地激活免疫细胞中的炎症小体， 可能会加剧疾病。但纳米材料-免疫细胞的综合表征 导致炎症小体激活和不需要的先天免疫反应的相互作用的研究很少 由于缺乏适当的调查工具。我的研究计划的总体愿景是设计 免疫工程平台将纳米科学和工程设计与免疫操纵联系起来 解决免疫学中的基本和转化问题的系统。我们专注于开发有效的 通过了解不同免疫系统成分之间的相互作用来制定免疫治疗策略， 各种纳米材料和免疫细胞之间的关系。具体来说，我们的目标是解决以下基本问题： 炎性体生物学以及纳米材料特性如何影响其与先天免疫细胞的相互作用 炎症小体激活。为了实现这一目标，我们建议设计一个多参数聚合物库 纳米材料平台在单个系统中具有多种表面和核心特性。这将使我们能够测试 这些纳米材料特性对炎症小体激活的影响，一次调整一种特性 发展纳米材料的结构-性能-功能关系。我们开发了新颖的高通量 成像平台能够实时监测炎症小体的激活。我们还设计了新颖的 成像探针实时监测体内炎症小体的激活。使用这些工具，在未来五年内， 我们的目标是了解纳米材料（基于聚合物）和免疫细胞（巨噬细胞、 单核细胞、树突状细胞和中性粒细胞）在炎症小体激活的背景下，并揭示 这种激活的体外和体内机制。总之，从这些研究中获得的信息可以 提供指导下一代纳米材料开发的设计标准，以控制、预防或 减轻炎症小体信号传导途径，并为调节炎症小体信号通路提供预测框架 炎症小体激活在诊断和治疗中的潜在应用。

Abstract: Inflammation is a defense mechanism triggered by innate immune system against any foreign invasion to restore homeostasis, but when it sustains for a prolonged period of several months to years, it transforms into a chronic condition resulting in several harmful diseases. The inflammasome is a hetero-multimeric protein complex known for activating inflammatory caspases followed by subsequent processing of cytokines, which makes it one of the key players during inflammation. Abnormal activation of inflammasomes can initiate undesirable inflammatory responses associated with the progression of chronic inflammatory diseases. Several studies have investigated nanomaterial interactions with immune cells to understand their role in various biological applications and tailor them to different needs. Indeed, several types of nanomaterials have been widely explored to target the immune cells at the disease site to modulate the immune responses. However, our recent studies and several recent reports suggest that many of these nanomaterials activate inflammasomes in immune cells non-specifically, potentially exacerbating the disease. But the comprehensive characterization of the nanomaterial-immune cell interactions that results in inflammasome activation and the unwanted innate immune response is poorly studied due to a lack of appropriate investigative tools. The overall vision of my research program is to design immunoengineering platforms bridging nanoscience and engineering design with manipulation of the immune system to address fundamental and translational questions in immunology. We focus on developing effective immunotherapy strategies by understanding the interactions between different immune system components, between various nanomaterials and immune cells. Specifically, we aim to address fundamental questions in inflammasome biology and how nanomaterial properties affect their interactions with innate immune cells and inflammasome activation. To accomplish this, we propose to engineer a library of multiparametric polymeric nanomaterial platform with various surface and core characteristics in a single system. This will allow us to test the effect of these nanomaterial properties on inflammasome activation, tweaking one property at a time to develop nanomaterial structure-property-function relationships. We have developed novel high-throughput imaging platform to enable monitoring of inflammasome activation in real time. We have also engineered novel imaging probes to monitor inflammasome activation in vivo in real time. Using these tools, over next five years, we aim to understand the interactions between nanomaterials (polymer-based) and immune cells (macrophages, monocytes, dendritic cells and neutrophils) in the context of inflammasome activation and uncover the mechanisms of this activation in vitro and in vivo. In summary, the information obtained from these studies could provide design criteria that guide the development of next-generation of nanomaterials to control, prevent or mitigate inflammasome signaling pathways and also provide a predictive framework for modulation of the inflammasome activation for potential applications in diagnostics and therapy.