MicroRNA-26b protects against MASH development in mice and can be efficiently targeted with lipid nanoparticles

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b ( ) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of in MASH and its therapeutic potential using mimic-loaded lipid nanoparticles (LNPs). , mice, and respective controls were fed a Western-type diet to induce MASH. Plasma and liver samples were characterized regarding lipid metabolism, hepatic inflammation, and fibrosis. Additionally, mimic-loaded LNPs were injected in mice to rescue the phenotype and key results were validated in human precision-cut liver slices. Finally, kinase profiling was used to elucidate underlying mechanisms. mice showed increased hepatic lipid levels, coinciding with increased expression of scavenger receptor a and platelet glycoprotein 4. Similar effects were found in mice lacking myeloid-specific . Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased in mice. Moreover, expression was increased by the deficiency, leading to more hepatic fibrosis. A murine treatment model with mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling upon deficiency, which was rescued by LNP treatment. Finally, mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices. Overall, our study demonstrates that the detrimental effects of deficiency in MASH can be rescued by LNP treatment. This novel discovery leads to more insight into MASH development, opening doors to potential new treatment options using LNP technology.