PROJECT SUMMARY/ABSTRACT Inflammation is a powerful, multifactorial host defense mechanism intended to protect the body from microbial insult and tissue damage. As such, inflammation is not only essential to the maintenance of homeostasis but is on its own deleterious when regulatory mechanisms go awry. Aberrant immune activation is prominent in human diseases and can contribute to the development of inflammatory (e.g. sepsis), autoimmune, and allergic conditions for which there are limited therapeutic options available that address the underlying immune dysfunction. The overarching goal of my research program is to elucidate fundamental and functional relationships between nanoparticle designs and biological responses in the context of inflammatory conditions. Indeed, nanoparticles can be designed with inherent immunomodulatory properties that can limit the extent of the inflammatory response through non-specific or antigen-specific mechanisms. Our group has made significant strides in both of these areas where we have shown that our custom-designed nanoparticles could blunt non-specific proinflammatory responses induced by multiple Toll-like receptor agonists in the absence of additional therapeutic agents. It was further demonstrated that these cargo-less nanoparticles improved survival in lethal mouse models of LPS-induced endotoxemia to 70%. Encapsulation of peptide or protein antigens into tolerogenic nanoparticles (tNPs) allows for the specific delivery of antigens to innate immune cells. Through manipulation of innate immune cell antigen presentation to T cells, the activation of antigen-specific T cells and disease progression was halted. tNPs were recently evaluated in a Phase I and II clinical trial for the treatment of celiac disease with success. The rapid progression of nanoparticles towards clinical implementation highlights the urgent need for mechanistic studies to elucidate the underlying principles that govern nanoparticle-based immunomodulation. We aim to address this need by capitalizing on our expertise in nanoparticle design and immune engineering, which includes polymer synthesis, nanoparticle formulation, and immunology. Over the next five years, we will specifically focus on how the physical and chemical properties of nanoparticles affect multiple outcomes associated with inflammatory responses using clinically-relevant in vitro and in vivo models of sepsis, autoimmunity, and allergy. The outcomes of these studies will enable us to establish a set of design rules that govern the immunomodulatory activity and interactions of nanoparticles and the immune system to guide the development and clinical translation of novel nanoparticles for inflammation and antigen-specific disease intervention. Through successful realization of our program, we will not only contribute to our understanding of the properties that are necessary for nanoparticles to interact with and internalize into immune cells but also develop a set of design ...