Fisetin loaded oral colon-targeted chitosan/chondroitin sulfate nanoparticles alleviate ulcerative colitis at different stages of severity.

Ulcerative colitis (UC) is a chronic inflammatory disease that needs lifelong treatment with medicines but cannot be cured. Additionally, harsh gastrointestinal environment often compromises the therapeutic effects of oral drugs. Fisetin (FIS) is a promising natural flavonoid that exhibits potent anti-inflammatory and antioxidant activities, but fails to translate into clinical benefits due to poor solubility and permeability. Here, we developed an oral colon-targeted nanoparticle formulation based on natural polysaccharides chitosan/chondroitin sulfate polyelectrolytes to deliver FIS (FIS@CS/ChS) to improve its bioavailability. FIS@CS/ChS possessed remarkable stability in a wide range of pH, and highly enhanced the colonic retention and mucus penetration of FIS. In both in vivo and in vitro studies, FIS@CS/ChS effectively promoted M2 macrophage polarization, attenuated inflammatory responses and oxidative stress, improved epithelial barrier function, and restored the gut microbial richness and diversity. As a result, this approach was significantly enhanced the therapeutic efficacy of FIS against UC across a range of severities, from mild to severe, and proved superior to conventional therapy with 5-aminosalicylic acid for these conditions. In conclusion, our data suggest that FIS@CS/ChS exclusively constituted by natural compounds represented a cost-effective, highly safe and minimally invasive therapy strategy to treat UC with different severity.