Orally Administrated Inflamed Colon-Targeted Nanotherapeutics for Inflammatory Bowel Disease Treatment by Oxidative Stress Level Modulation in Colitis

Inflammatory bowel disease (IBD) is an autoimmune disease that is characterized by excessive gastrointestinal tract inflammation. Although the exact cause of IBD remains unclear due to its multifactorial nature, it is believed to result from the inappropriate and continuous inflammatory immune responses that lead to prolonged gut microenvironment inflammation. Therefore, current clinical therapies for IBD primarily focus on blocking specific molecules involved in inflammation. However, the efficacy of these treatments varies significantly among individuals, and they often cause inflammation reoccurrence. Thus, there is a high demand for safe and targeted therapy that can be orally administered for effective IBD treatment. Characteristics of colonic inflammation include high expression of the positively charged protein on gut epithelial cells, indicating that negatively surface-charged formulation could target to inflamed lesions through oral administration. Hence, we aimed to design the use of inflamed colon-targeted antioxidant nanotherapeutics (ICANs) with high durability in gastrointestinal tract for <i>in situ</i> oxidative stress level modulation in colitis. ICANs consist of mesoporous silica nanoparticle (MSN) with surface-attached ROS-scavenging ceria nanoparticles (CeNPs), which are further coated with poly-acrylic acid (PAA) to facilitate preferential adherence to inflamed colon tissues through electrostatic interaction. We achieved a high ROS-scavenging property and negative surface charge that remained effective even after artificial gastrointestinal fluid incubation by optimization of the molecular weight and PAA-coating pH. Orally administrated ICANs demonstrated enhanced adherence to inflamed colon tissues in an acute inflammation mouse model of IBD induced by dextran sulfate sodium. Furthermore, administration of ICANs led to recovery of body weight, decreased levels of pro-inflammatory cytokines and CD11b⁺ cell infiltration, and restoration epithelial barriers against colitis. These data suggest that targeted delivery of ROS-scavenging nanotherapeutics led to modulation of pro-inflammatory gut microenvironment by regulating redox balance and reducing inflammatory cell infiltration, thereby suppressing the colitis-associated immune response. These findings highlight the potential of non-invasive ICANs as a promising candidate for treating inflammatory intestinal diseases by oxidative stress level modulation in colitis.