Oral delivery of IL-22 mRNA-loaded lipid nanoparticles targeting the injured intestinal mucosa: A novel therapeutic solution to treat ulcerative colitis

Oral mRNA delivery is a promising yet understudied approach for treating inflammatory bowel disease (IBD). Inspired by the colon-targeting ability of ginger-derived nanoparticles (GDNPs), we reversely engineered lipid nanoparticles that comprise the three major lipids identified in GDNPs. When mixed at the ratio found in GDNPs, the selected lipids (phosphatidic acid, monogalactosyldiacylglycerol, and digalactosyldiacylglycerol; 5:2:3) self -assembled into new lipid nanoparticles (nLNPs) in phosphate-buffered saline. We encapsulated IL-22-mRNA within the nLNPs, as enhanced IL-22 expression in the colon is known to have potent anti-inflammatory effi-cacy against ulcerative colitis (UC). The IL-22 mRNA-loaded nLNPs (IL-22/nLNPs) were found to be about 200 nm in diameter and have a zeta potential of-18 mV. Oral delivery of IL-22/nLNPs elevated the protein expression level of IL-22 in the colonic mucosa of mice. In a mouse model of acute colitis, mice fed with IL-22/ nLNPs experienced an accelerated healing process, as indicated by the recovery of more body weight and colon length as well as reduction of the histological index, colonic MPO activity, fecal lipocalin concentration, and mRNA expression levels of pro-inflammatory cytokines (TNF-alpha, IL-6, and IL-1 beta). Our results suggest that our reversely engineered nLNPs is an excellent mRNA delivery platform for treating ulcerative colitis.