Multiscale considerations for immune engineering at mucosal interfaces

项目摘要 弗罗曼实验室的长期目标是开发个性化的免疫调节性粘膜疗法 使用粒子免疫工程。粘膜表面排列在呼吸道、胃肠道和泌尿生殖道上。 并成为阻止外国入侵的第一道屏障。这些界面是粘膜免疫系统的家园，一个 宿主免疫保护的专门手臂，在这些关键屏障上维持平衡。专用牢房 在粘膜上调节共生菌并保持耐受性，同时也增加了对战斗的反应 病原体感染。在过去的二十年里，工程粒子平台已经成为一种方便的 与先天免疫细胞相互作用的方式，提供精确的化学线索和病原体模拟能够 指示免疫反应。尽管有压倒性的潜力可以直接调节粘膜免疫功能 在这些重要的界面上，迄今为止在粒子免疫工程方面的大多数进展都绕过了 完全是粘膜界面，而不是专注于非肠道给药途径。有一种迫切的需要 为了开发专门针对粘膜环境设计的粒子免疫工程方法， 这可以克服粘膜给药所面临的独特的多尺度障碍。大体上讲，有两个主要的 在粘膜界面上必须解决的颗粒驱动免疫工程的挑战 需要的翻译进展：1)克服粘膜免疫系统的动态屏障功能和 2)针对黏膜抗原提呈细胞(APC)量身定做有效的刺激线索 回应。弗罗曼实验室将我们的短期目标集中在这两个方面取得根本性进展 挑战领域，特别是使用呼吸道作为粘膜系统的模型。迄今为止的主要进展 已经包括对呼吸道内用于肺APC调节的新型纳米颗粒平台的评估， 发现粒子驱动的调节延长了APC的寿命，并创建了全尺寸呼吸模型系统。在……里面 在这项提案中，我们将继续努力设计个性化的免疫调节性粘膜疗法。 我们将继续在化学-生物界面开发控制细胞-APC相互作用的工具，并 随后的细胞和微环境反应。我们将同步推进宏观交通 模型弥合器官水平和粘膜微环境运动之间的差距，这将促进 生理学应用。这些未来的努力非常适合研究计划，因为广泛的 适用的多尺度实验框架，以应对动态 人体的粘膜界面。

Project Summary The long-term goal of the Fromen lab is to develop personalized immunomodulatory mucosal therapeutics using particle immune engineering. Mucosal surfaces line the respiratory, gastrointestinal, and urogenital tracts and serve as the first barrier to foreign invasions. These interfaces are home to the mucosal immune system, a specialized arm of the host immune protection that maintains balance at these critical barriers. Dedicated cells at the mucosa regulate commensal bacteria and maintain tolerance, while also mounting responses to combat pathogenic infections. In the past two decades, engineered particle platforms have emerged as a convenient way to interact with innate immune cells, providing precise chemical cues and pathogen mimicry capable of instructing immune response. Despite the overwhelming potential to directly regulate mucosal immune function at these essential interfaces, most advances to date in particle-inspired immune engineering have bypassed the mucosal interface altogether and instead focused on parenteral routes of administration. There is a critical need to develop particle immune engineering approaches that are designed specifically for the mucosal environment, that can overcome the unique multiscale obstacles faced in mucosal drug delivery. Broadly, there are two major challenges of particle-driven immune engineering at mucosal interfaces that must be addressed to generate needed translational advances: 1) overcoming the dynamic barrier function of the mucosal immune system and 2) tailoring effective stimulatory cues specifically to mucosal antigen presenting cells (APCs) for desirable responses. The Fromen lab has focused our short-term goals on generating fundamental advances in these two challenge areas, specifically using the respiratory tract as a model mucosal system. Major advances to date have included evaluation of novel nanoparticle platforms within the respiratory tract for lung APC modulation, discovery of particle-driven regulation over APC lifespan, and creation of full-size respiratory model systems. In this proposal, we will continue our efforts to engineer personalized immunomodulatory mucosal therapeutics. We will continue to develop tools at the chemical-biology interface that control cellular-APC interactions and subsequent cellular and microenvironment response. We will simultaneously advance macroscopic transport models to bridge the gap between organ-level and mucosal microenvironment motion that will advance multiple physiological applications. These future efforts are well suited to the research program, given the widely applicable multiscale experimental framework to address the broad challenges presented by the dynamic mucosal interfaces of the human body.