Oral Delivery of Chitosan-Rosmarinic Acid Nanoparticles Ameliorates Mucosal Inflammation in a Mouse Model of Colitis

Inflammatory bowel disease (IBD) is a chronic disorder characterized by intestinal barrier dysfunction, excessive immune activation, and oxidative stress. Current treatment options, such as 5-aminosalicylic acid (5-ASA), exhibit limited therapeutic efficacy due to poor bioavailability and inability to restore intestinal homeostasis. Herein, a novel nanomedicine that can be orally administered, low-molecular-weight chitosan-conjugated rosmarinic acid nanoparticles (LMWC-RANPs), designed to enhance IBD treatment through its mucoadhesive, antioxidant, and immunomodulatory properties, are introduced. LMWC-RANPs exhibit strong mucoadhesion, leading to prolonged retention in the inflamed gastrointestinal tract and efficient ROS scavenging. In a DSS-induced mouse model of colitis, LMWC-RANPs significantly alleviate disease symptoms by reducing body weight loss, preserving colon length, and restoring intestinal barrier integrity. Additionally, LMWC-RANPs effectively modulate the mucosal immune response by promoting macrophage polarization from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes and reducing Th17 cell populations while enhancing regulatory T cell (Treg) frequencies. Furthermore, oral administration of LMWC-RANPs exhibits no observable systemic toxicity in healthy mice, as confirmed by hematological and histopathological analyses. Collectively, these findings demonstrate the potential of LMWC-RANPs as a safe and effective therapeutic for inflammatory bowel disease, with broader implications for other gut-associated inflammatory diseases.