NANOSCALE EXOSOMES FROM BROCCOLI SPROUTS IMPROVE THE TARGETED DELIVERY AND THERAPEUTIC EFFICACY OF BIOACTIVES AGAINST INFLAMMATORY BOWEL DISEASE

Inflammatory bowel disease (IBD) is an incurable gastrointestinal (GI) condition characterized by chronic inflammation with multifactorial and poorly understood pathophysiology. Patients with IBD are at a significantly increased risk of developing colorectal dysplasia and colorectal cancer. Although the pathogenesis of IBD is not fully understood, the prevailing model is that it is due to combined genetic and environmental factors disrupting epithelial barrier integrity and host immune responses. One complementary strategy to manage IBD is to incorporate dietary changes that modulate inflammatory pathways and improve gut barrier function to reduce the severity of IBD. Dietary factors can have significant effects on both immune and epithelial homeostasis. There is evidence, at least in mice, that some bioactives, in particular isothiocyanates, from cruciferous vegetables, may improve intestinal barrier function, have anti- inflammatory activities, and confer protective effects against the development of colitis.Although efficacies of dietary bioactives have been demonstrated, poor stability and/or untargeted delivery often limit their development and clinical efficacy. Exosomes, the nanoscale vesicles released from cells, have been shown to possess prominent characteristics of enhancing drug stability and targeting various diseases. Diet-derived exosomes contain endogenous bioactives and have improved stability for therapeutic applications. Exosomes enter cells via transcytosis to release loaded bioactives, which may improve cellular uptake and retention as compared to dietary bioactives alone. More importantly, nanomedicine has proven to have enhanced permeability and retention (EPR) effects in tumors and inflamed tissues. Thus, plant cell-derived exosomes are more promising vehicles to improve the inflammation-targeted delivery and efficacy of dietary bioactives.Our central hypothesis is that broccoli sprouts-derived exosomes (BSDExo) can protect dietary bioactives from early release in the upper GI tract and confer targeted delivery of bioactives to inflamed tissues in IBD. The current proposal aims to address the knowledge gap on whether and how naturally diet-based nanoscale exosomes can prevent and treat IBD. Our long-term goal is to develop a natural nanomedicine from whole food to complement current therapeutic options for IBD patients. Collaboration among the PD, Co-PD, and Co-I combines expertise in nanoparticles/exosomes, drug discovery, dietary bioactives for disease prevention, and evaluation and prediction of drug distribution. After obtaining more data from this pilot project, the PD, Co-PD, and Co-I will apply for a standard research grant application to the AFRI program A1343. The following objectives are proposed for this study:Objective 1: To assess the targeted delivery of BSDExo to inflammatory colon cells and tissues.1.1 To assess the stability and release of dietary bioactives from BSDExo in simulated biorelevant GI fluids.1.2 To investigate the cellular uptake mechanisms of BSDExo in colon cells.1.3 To determine the targeting and retention of BSDExo in inflamed GI tissues in a chemically induced colitis mouse model.Objective 2: To evaluate the therapeutic effects of BSDExo against colitis.2.1 To examine the anti-inflammatory effect of BSDExo in a human colitis-on-a-chip model.2.2 To evaluate the efficacy of BSDExo in a chemically induced colitis mouse model.