Abstract Over 3 million U.S. adults are diagnosed with inflammatory bowel disease (IBD). The current IBD therapies, such as immunosuppressants and biologics, treat the symptoms of IBD; however, they generally do not address the underlying causes, including defective intestinal barrier functions, abnormal levels of pro-inflammatory cytokines and immune cells, and dysregulated gut commensal microbes. Thus, there exists a critical need for new approaches for treatment of IBD. Moreover, gut microbiome is emerging as the next frontier in drug development. However, it remains unknown how to effectively regulate the gut microbiome for therapeutic purposes. Our long- term research goal is to develop new gut-targeted strategies for modulating innate immunity and gut microbiome. Our objectives in this application is to generate new fundamental knowledge on biomaterial parameters for efficient targeting of inflamed colon and subsequent restoration of intestinal barrier functions and healthy gut microbiota in IBD. Toward this goal, we have developed a new biomaterial system that can target inflamed colon and initiate healing responses in inflamed colonic epithelium. Here, using our biomaterial system as a starting platform, we seek to uncover new materials criteria for designing biomaterials for optimal colon targeting (Aim 1), regulation of innate immunity (Aim 2), and modulation of the gut microbiota (Aim 3) in the context of IBD. Overall, successful completion of our proposal will enable colon-targeted drug delivery systems that will exert potent efficacy against IBD.