Glucocorticoids (GCs) are the primary treatment for ulcerative colitis (UC), but their long-term use is associated with severe systemic toxicity and side effects. Local delivery via enema can enhance GC concentrations at the site of inflammation in the distal colon while minimizing systemic exposure. However, frequent diarrhea in UC patients often shortens colonic residence time, limiting the therapeutic efficacy of GCs.This study aimed to develop mucoadhesive nanoparticles (NPs) carrying different dexamethasone derivatives (DDs) that can adhere to the positively charged inflamed colonic mucosa through electrostatic interactions after enema administration, thereby increasing local drug concentration and achieving targeted therapy for UCTwo dexamethasone derivatives, dexamethasone hemisuccinate and dexamethasone phosphate, were synthesized. Core PEI-DDs NPs were prepared via electrostatic interaction between the cationic polymer polyethyleneimine (PEI) and DDs. Subsequently, the natural polyanionic polysaccharide sodium alginate (SA) was coated onto the NP surface to form SA-PEI-DDs NPs. The formulations were characterized for in vitro stability, drug release, and colonic mucosal adhesion both in vitro and in vivo. Therapeutic efficacy was evaluated in TNBS-induced colitis mice by monitoring body weight, disease activity index (DAI), myeloperoxidase (MPO) activity, pro-inflammatory cytokine levels, and histopathological changes via hematoxylin and eosin staining.The structures of the DDs were confirmed by 1H-NMR and MS. The NPs exhibited negative surface charges, high drug loading efficiency, and particle sizes that differed significantly between formulations. They showed good stability and sustained drug release under simulated colonic conditions. The negative surface charge promoted adhesion to positively charged inflamed mucosa, enhancing local retention of the NPs at the colitis site. In vivo, SA-PEI-DDs NPs demonstrated superior therapeutic effects compared to free dexamethasone in TNBS-induced colitis mice.Mucoadhesive SA-PEI-DDs nanoparticles represent a promising nano-enema strategy for UC, enabling enhanced colonic targeting, prolonged drug retention, and improved therapeutic outcomes.
