PH Response Oral nanoparticle PHPP-Eud improves intestinal barrier and microbiota balance by activating FoxO4 to alleviate ulcerative colitis

Ulcerative colitis (UC) is recognized as a significant health concern due to its complex pathogenic factors and the challenges associated with its treatment. Oral administration is considered the most promising approach for UC therapy, necessitating the development of a safe and effective treatment capable of withstanding the gastrointestinal environment. In this study, a pH-responsive oral nanoparticle, PHPP-Eud, was developed using the emulsion-solvent evaporation and nanoprecipitation methods. Its therapeutic efficacy was evaluated through in vitro cell models and in vivo studies using DSS-induced UC mice. The results demonstrated that PHPP-Eud exhibited strong resistance to gastric acid, while pro-inflammatory M1 macrophages were inhibited and anti-inflammatory M2 macrophages were promoted. Moreover, excellent biological stability and safety were observed in vivo. UC was alleviated through intestinal barrier repair, gut microbiota balance restoration, intestinal metabolite modulation, inhibition of the PI3K-AKT inflammatory pathway, and activation of the FoxO pathway.