Multiscale considerations for immune engineering at mucosal interfaces

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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.