Triptolide loaded cerium oxide nanozyme based oral nanoplatform for targeted colitis therapy

Ulcerative colitis (UC) is a type of colonic inflammation characterized by immune dysregulation and intestinal inflammation. Cerium oxide (CeO₂) nanozyme can effectively downregulate reactive oxygen species (ROS), but it lacks anti-inflammatory and other pharmacological activities. Triptolide (TP) has anti-inflammatory, antioxidant, antifibrotic, and autophagy-regulating pharmacological properties. However, severe gastrointestinal side effects hinder its clinical application. Therefore, this study aimed to develop TP-loaded CeO₂ nanozymes (T-C). T-C effectively reduces ROS at sites of colitis. In addition, chitosan, chondroitin sulfate, and pectin were employed as carriers to construct T-C-loaded nanoparticles (T-C@pNP), in which chitosan promoted nanoparticle assembly, chondroitin sulphate enhances uptake of nanoparticle, and pectin enabled pectinase-responsive release, resulting in a novel oral nanoplatform for colitis treatment. In a mouse colitis model, T-C@pNP significantly alleviated inflammation-induced weight loss, colon shortening, and colon damage, demonstrating notable therapeutic effects. T-C@pNP not only downregulated ROS, but also reduced the levels of proinflammatory factors (TNF-α, IL-6, and IFN-γ)， possibly through inhibition of the nuclear factor kappa-B (NF-κB) pathway, and diminished neutrophil infiltration. Furthermore, it regulated macrophage polarization, potentially alleviated inflammation-associated fibrosis, and disrupted the vicious cycle of inflammation. Moreover, T-C@pNP may activate epithelial cell autophagy, enhance the intestinal mucus barrier, promote the expression of ZO-1 and occludin, and partially modulate the gut microbiota composition, thereby improving intestinal barrier repair. In conclusion, complemented by satisfactory anti-inflammatory and biosafety results, this nanoplatform represents a promising treatment option for colitis in rats.