Quercetin-loaded milk-derived extracellular vesicles for the treatment of inflammatory bowel disease by alleviating senescence-associated cell cycle arrest

Inflammatory bowel disease (IBD) is characterized by excessive inflammation, ROS accumulation, barrier dysfunction, and microbiota imbalance, though its etiology remains unclear. Studies have confirmed that excessive ROS accumulation at inflammatory sites contributes to disease progression by inducing cellular senescence. We found that IBD pathological micro-environment is accompanied by cellular senescence of colonic epithelial cells, which may be caused by cell cycle arrest. To target ROS-induced cellular senescence, we employed the milk-derived extracellular vesicles (Ev) to achieve optimal quercetin (Que) encapsulation, namely Eq. In vitro cell experiments confirmed that Eq could be internalized by colonic epithelial cells mainly through clathrin-mediated endocytosis, which not only displayed potent ROS-scavenging capability, but also effectively mitigated the senescence of intestinal epithelial cell and reversed the cell cycle arrest. In mice model of Dss-induced colitis, orally-administered Eq exhibited good gastrointestinal stability and facilitated the targeted Que delivery to the intestinal inflamed lesions. Importantly, orally-administered Eq terminated the vicious cycle of inflammation-ROS-senescence by suppressing the p53/p21 pathway, thereby significantly attenuating the intestinal barrier dysfunction and impaired cell proliferation. Transcriptomic analysis further revealed that Eq exerted anti-senescence effects by reversing the proliferation arrest and reconstructing the cell cycle. Collectively, this study is the first report on the promising potential of orally-administered nanotherapeutics of anti-aging effect for IBD treatment. Eq may serve as an innovative strategy for the IBD and other inflammation and aging related diseases.