MiR-29a-loaded nanoparticles alleviate inflammatory bowel disease via Sgk1/Foxo3a axis

Inflammatory bowel disease (IBD) is an autoimmune disease with a long course, numerous complications, and high disability, and its incidence continues to grow worldwide. microRNA-29a (miR-29a) has the potential to regulate inflammation and fibrosis. However, identifying the targets and designing suitable delivery vectors remain major obstacles in the development of miRNA-based drugs. Layered double hydroxide (LDH), which has the biological function of suppressing immune response, is an excellent miRNA carrier. In this study, miR-29a was enclosed in LDH, which enhanced the transfection efficiency and extended the residence of miR-29a in tissues. With elevated lipopolysaccharide (LPS) concentration, LDH@miR-29a showed better inhibition of inflammatory factors and reactive oxygen species in bone marrow-derived macrophages than LDH alone. In addition, the pro-fibrotic effect of transforming growth factor-β1 (TGF-β1) was reduced in NIH-3 T3 cells incubated with LDH@miR-29a. Transcriptome sequencing indicated that LDH@miR-29a significantly decreased Sgk1 and increased the nuclear localization of Foxo3a in both pro-inflammatory and pro-fibrotic environments, suggesting that Sgk1 is a target gene of miR-29a. Furthermore, murine models of colitis and intestinal fibrosis were ameliorated after LDH@miR-29a treatment. These results demonstrate that the Sgk1 and FoxO signaling pathways play important roles in the mechanism of nanocomplexes. This work shows that combining LDH with miR-29a, provides a simultaneous anti-inflammatory and anti-fibrotic approach for treating of IBD.