**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** INFLAMMATORY BOWEL DISEASE (IBD) IS AN INCURABLE GASTROINTESTINAL (GI) CONDITION CHARACTERIZED BY CHRONIC INFLAMMATION WITH MULTIFACTORIAL AND POORLY UNDERSTOOD PATHOPHYSIOLOGY. THE NANOSCALE EXOSOMES HAVE BEEN SHOWN TO POSSESS PROMINENT CHARACTERISTICS OF ENHANCING DRUG STABILITY IN THE GI TRACT AND TARGETING INFLAMMATION. 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 TO INFLAMED TISSUES IN IBD. OUR LONG-TERM GOAL IS TO DEVELOP A NATURAL NANOMEDICINE FROM THE WHOLE FOOD TO COMPLEMENT CURRENT THERAPEUTIC OPTIONS FOR IBD PATIENTS. OBJECTIVE 1 IS TO DETERMINE THE TARGETED DELIVERY OF BSDEXO TO INFLAMMATORY COLON CELLS AND TISSUES. WE WILL ASSESS THE STABILITY AND RELEASE OF DIETARY BIOACTIVES FROM BSDEXO IN SIMULATED GI FLUIDS, CHARACTERIZE BSDEXO SURFACE MARKERS, INVESTIGATE THE UPTAKE MECHANISMS OF BSDEXO IN COLON CELLS, AND DETERMINE THE TARGETING AND RETENTION OF BSDEXO IN INFLAMED GI TISSUES IN A CHEMICALLY INDUCED COLITIS MOUSE MODEL. OBJECTIVE 2 IS TO EVALUATE THE THERAPEUTIC EFFECTS OF BSDEXO AGAINST COLITIS. WE WILL MEASURE THE TRANSCRIPT AND PROTEIN LEVELS OF PROINFLAMMATORY CYTOKINES UPON BSDEXO TREATMENT IN A HUMAN COLITIS-ON-A-CHIP MODEL, AND ASSESS DISEASE ACTIVITY INDEX, LIPOCALIN LEVELS, COLITIS HISTOLOGY, AND THE TRANSCRIPT AND PROTEIN LEVELS OF PROINFLAMMATORY CYTOKINES IN A CHEMICALLY INDUCED COLITIS MOUSE MODEL. THIS PROJECT ADDRESSES THE PROGRAM AREA A1343 FOOD AND HUMAN HEALTH THROUGH INVESTIGATING THE FUNCTION AND EFFICACY OF DIET-DERIVED, BIOACTIVE-CONTAINING NANOSCALE STRUCTURE FOR HUMAN GUT HEALTH.