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.