Orally hierarchical targeting delivery systems relieve colitis by protecting host mitochondria and modulating gut microbiota

The overproduction of reactive oxygen species (ROS) for mitochondrial damage and dysbiosis of gut microbiota strongly aggravates inflammatory bowel disease (IBD). However, bacteria are mainly distributed in "outer" apical side of colonic epitheliums in colonic lumen while mitochondria are located in "inner" colonic cells (like macrophages and epitheliums), which limited the precise drug delivery. Here, we propose an orally hierarchical targeting platform containing natural antioxidant—resveratrol and dietary prebiotics—inulin to simultaneously regulate host mitochondria and gut microbiota. We find that the platform exhibits hierarchical targeting delivery: 1) inulin gel retains in colonic lumen for modulating gut microbiota with specifically enriching probiotics; 2) resveratrol loaded mitochondria-targeting liposomes sustainedly released from inulin gel are uptaken by macrophages and epitheliums; 3) liposomes accumulate in mitochondria of macrophages and epitheliums for ROS scavenging and wound healing. Furthermore, such delivery systems promoted cooperation between microbiota and mitochondria—the up-regulated probiotics enhance the production of butyric acid which provides energy source for mitochondria in epitheliums, and the protected mitochondria facilitate the restitution of colonic mucosa to resist gut bacteria invasion. Collectively, the orally platform enabling gut microbiota and colonic mitochondria targeting delivery in a cascade manner facilitate the alleviation of IBD.