Engineered extracellular vesicles with surface FGF21 and enclosed miR-223 for treating metabolic dysfunction-associated steatohepatitis

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder with a complex pathogenesis that requires combination therapies rather than monotherapies. Extracellular vesicles (EVs) exhibit inherently efficient delivery to the liver and can be engineered to carry various therapeutic substances, making them promising agents. In this study, EVs were engineered to display fibroblast growth factor 21 (FGF21) on their surface and encapsulate miR-223 (223/F-EVs), aiming to improve steatosis and alleviate inflammation and fibrosis, respectively. Introducing the 223/F-EVs into human liver cell lines significantly reduced both basal and induced levels of lipid storage, inflammation, and fibrosis markers. Furthermore, using an FGF21-blocking antibody or miR-223 inhibitor effectively diminished the efficacy of the 223/F-EVs, confirming the essential roles of FGF21 and miR-223 in these processes. In a Choline-Deficient, l-Amino acid-defined, High-Fat Diet (CDAHFD)-fed mouse model, intravenously administered 223/F-EVs demonstrated liver-preferential delivery and a marked reduction in the MASH phenotype without compromising bone density, unlike conventional FGF21 treatment. Collectively, 223/F-EVs convey FGF21 and miR-223 exclusively to the liver, offering strategic advantages by mitigating MASH progression via multiple pathways. This study lays a solid foundation for further investigation of engineered EVs as a transformative therapeutic approach for treating MASH.

Keywords: Combination therapies; Extracellular vesicles; Fibroblast growth factor 21; Metabolic dysfunction-associated steatohepatitis; Micro-RNA.