Project Summary/Abstract Inflammatory bowel diseases (IBD) affect over 1.5M people in the US and despite the wide array of treatment options for maintaining remission in ulcerative colitis (UC), significant risks of infection and malignancy accompany otherwise effective biological agents. Locally-delivered small molecule therapies, such as second-generation glucocorticoids exemplify the unique advantage of targeted delivery to improve therapeutic efficacy while reducing systemic toxicity in UC. Many biologics that are used for treatment of IBD (e.g., anti-TNFα therapies), enable pleiotropic responses in the gastrointestinal (GI) tract to induce and maintain remission in IBD patients; however, these biologics necessitate systemic delivery as opposed to local delivery and remain costly with rising estimates of $50,000 – $150,000 in drug acquisition costs per year. In addition to the desire for affordable therapies, there is an urgent need for technologies that improve local targeting of biologics to the large intestine due to higher efficacy, less off-target effects, and a substantial reduction in drug required to achieve an effect. Specific technical challenges remain which have prevented implementation of intestine-targeted oral delivery systems for biologics including: (1) inactivation of biologics by enzymes, stomach acids, bile, digestive process, etc., (2) shelf- stability of biologics in oral dosage forms, (3) lack of spatial access to discrete sites of inflammation upon release in the intestines, and (4) consistent and reliable delivery at the target site. To address these challenges, we have recently developed platform delivery systems for dietary proteins as well as sensitive biologics that are capable of sustained release over a 24-hour period in physiological situations, enabling protection against harsh conditions in the GI tract, and compatible with a variety of proteins tested to date. This proposal aims to expand this platform to protect therapeutic proteins (biologics) so as to enable their targeted oral delivery to the intestines. Our initial investigation will focus on rhPRG4, a large protein involved in epithelial lubrication, towards treating the symptoms of UC. Specifically, we aim to formulate rhPRG4 to protect against bile salts, enzymes, acids, moisture, and light with a targeted delivery to the colon. Furthermore, we will assess viability of released rhPRG4 to reduce cytokine production in an in vitro model of inflammation