PROJECT SUMMARY/ABSTRACT Despite continual improvement in the treatment of inflammatory bowel disease (IBD), achieving mucosal healing remains difficult for many patients with IBD. A key hallmark of IBD is a compromised mucosal barrier leading to erosions and ulcerations of the epithelium, which result in increased epithelial permeability and uncontrolled immune response that induce and maintain intestinal inflammation. A healed and intact mucosa is essential for preventing bacterial translocation from the lumen and modulating immune response to regain intestinal homeostasis. However, limited success has been achieved for complete mucosal healing, likely due to premature loss of drug efficacy and the off-target effect in normal tissue. Moreover, there remains a lack of clear understanding on the complex healing process of the inflamed mucosa. Under chronic inflammation, how the immune system and the microbiota may interfere with epithelial repair, thereby hindering healing, is largely unknown. Therefore, there is a critical need for strategies that can target the inflamed mucosa to identify key mediators in epithelial repair and promote healing. Without such strategies, mucosal healing will continue to be a “therapeutic ceiling”. To address this challenge, we propose to engineer a biomaterial-based biomimetic system that can selectively target the inflamed mucosa and locally release therapeutics to the damaged epithelium. This system comprises a polymer-based hydrogel and drug-loaded nanoparticles (NPs)—a hydrogel will create an interface at the inflamed mucosa, acting as a synthetic mucus layer, and the NPs will release drugs locally to suppress bacteria, resolve inflammation, and repair the epithelium. Our previous study showed that negatively charged hydrogels preferentially adhered to the inflamed mucosa based on charge-mediated interaction in murine models of colitis and IBD patient biopsies. This proposed research will combine the charge-based interaction with sol-to-gel transition using functionalized thermo-responsive polymers to enhance the selective targeting. The NPs provide a platform for loading different drugs or drug combinations to tackle the complex healing process at the site of inflammation. The overall objective of this project is to maximize healing of the inflamed mucosa, enabled by drug delivery mimicking the natural mucosal barrier and uncovering key mediators that regulate epithelial repair. The rationale is that determining therapeutic efficacy of our biomimetic drug delivery system in preclinical models of IBD will provide a strong scientific framework whereby new approaches to maximize mucosal healing can be developed. In this project, we will pursue three specific aims: 1) a polymer-based synthetic mucus layer will be characterized and optimized, 2) combinatorial NP drug delivery will be used to detect key mediators regulating epithelial repair, and 3) therapeutic efficacy and mucosal healing by the drug-loaded biomim...