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粘膜疗法 使用粒子免疫工程。呼吸道、胃肠道和泌尿生殖道的粘膜表面 成为抵御外敌入侵的第一道屏障这些界面是粘膜免疫系统的家园， 宿主免疫保护的专门手臂，在这些关键屏障上保持平衡。专用单元格 在粘膜调节肠道菌群和保持耐受性，同时也安装反应，以打击 病原性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， 指导免疫反应。尽管直接调节粘膜免疫功能的潜力巨大， 在这些重要的界面上，迄今为止粒子激发的免疫工程的大多数进展都绕过了 粘膜界面，而是集中在肠胃外给药途径。迫切需要 为了开发专门为粘膜环境设计的颗粒免疫工程方法， 其可以克服粘膜药物递送中所面临的独特的多尺度障碍。大体上，有两个主要的 必须解决的粘膜界面处的颗粒驱动免疫工程的挑战， 需要的转化进展：1）克服粘膜免疫系统的动态屏障功能， 2)定制特异性针对粘膜抗原呈递细胞（APC）的有效刺激因子， 应答弗罗曼实验室将我们的短期目标集中在这两个方面的根本性进展上 挑战区域，特别是使用呼吸道作为模型粘膜系统。迄今取得的重大进展 包括评估呼吸道内用于肺APC调节的新型纳米颗粒平台， 发现APC寿命的颗粒驱动调节，并创建全尺寸呼吸模型系统。在 根据这一建议，我们将继续努力设计个性化的免疫调节粘膜治疗剂。 我们将继续开发化学-生物学界面的工具，控制细胞-APC相互作用， 随后细胞和微环境响应。我们将同时推进宏观交通 模型，以弥合器官水平和粘膜微环境运动之间的差距， 生理应用。这些未来的努力非常适合研究计划，考虑到广泛的 适用的多尺度实验框架，以解决动态提出的广泛挑战 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.