BACKGROUND: Inflammatory bowel disease (IBD) is a chronic condition marked by recurring intestinal inflammation, leading to symptoms such as fatigue, diarrhea, and weight loss. Current treatments are limited, highlighting the need for new therapeutic strategies. beta-Carotene (BC), a natural antioxidant, has potential in managing colitis, but its low bioavailability limits its efficacy. This study evaluated a novel BC-loaded sesame protein hydrolysate nanoparticles (BC-SPH NPs) formulation to enhance BC bioavailability and therapeutic performance in a dextran sodium sulfate (DSS)-induced colitis model. RESULTS: BC-SPH NPs showed an average size of 50.30 +/- 0.43 nm, an encapsulation efficiency of 75.23 +/- 0.92%, a prolonged plasma residence profile, with a time to reach maximum plasma concentration (T(max)) of 8 h, and a peak plasma concentration of 64.982 ng mL(-1). Notably, the NPs enabled enhanced tissue distribution of BC to key tissues in rats including kidneys, liver, small intestine, and colon. In DSS-induced colitis mice, BC-SPH NPs significantly reduced disease activity index, improved body weight, preserved colon length and structure, and prevented inflammatory cell infiltration. Additionally, BC-SPH NPs lowered serum interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha), as well as colonic myeloperoxidase (MPO) activity and nitric oxide (NO) levels. Furthermore, BC-SPH NPs up-regulated tight junction proteins Claudin-1, ZO-1, and Occludin, indicating improved intestinal barrier integrity. In contrast, free BC provided only modest effects. CONCLUSION: This study demonstrates that BC-SPH NPs substantially enhance the bioavailability and therapeutic effects of BC in DSS-induced colitis compared to free BC. The nanoformulation effectively alleviates colitis symptoms, preserves intestinal integrity, and reduces inflammation, suggesting that BC-SPH NPs represent a promising natural therapeutic option for the prevention and treatment of ulcerative colitis. (c) 2025 Society of Chemical Industry.