Functional Ginger-Derived\nExtracellular Vesicles-Coated\nZIF‑8 Containing TNF‑α siRNA for Ulcerative Colitis\nTherapy by Modulating Gut Microbiota

Tumor necrosis factor-α (TNF-α) plays a causal\nrole\nin the pathogenesis of ulcerative colitis (UC), and anti-TNF-α\nsiRNA shows great promise in UC therapy. However, delivering siRNA\nwith site-targeted stability and therapeutic efficacy is still challenging\ndue to the complex and dynamic intestinal microenvironment. Here,\nbased on the functional plant-derived ginger extracellular vesicles\n(EVs) and porous ZIF-8 nanoparticles, we propose a novel TNF-α\nsiRNA delivery strategy (EVs@ZIF-8@siRNA) for UC targeted therapy.\nGinger EVs show strong colon and macrophage targeting, as well as\nrobust resistance to acidic degradation in the stomach. Moreover,\n 6-shogaol in ginger-derived EVs displays anti-inflammatory effects,\nwhich enhance the treatment efficiency by cooperation with TNF-α\nsiRNA. <i>In vitro</i> experiments reveal that ZIF-8 nanoparticles\nhave high TNF-α siRNA loading capacity and promote siRNA escape\nfrom cellular lysosomes. <i>In vivo</i> experiments show\nthat the TNF-α level is reduced more significantly in colonic\ntissue than other nontargeted inflammation related factors, showing\na good targeting of this composite nanoparticle. Furthermore, gut\nmicrobiota sequencing results demonstrate that the nanoparticles can\npromote intestinal barrier repair by regulating the intestinal microbial\nbalance and restoring the intestinal health of UC mice. Therefore,\nthe developed EVs@ZIF-8@siRNA nanoparticles may represent a novel\ncolon-targeted oral drug, providing a promising therapeutic strategy\nfor UC therapy.