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

Background & Aims. The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (miR-26b) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of miR-26b in MASH and its therapeutic potential using miR-26b mimic-loaded lipid nanoparticles (LNPs). Methods. Apoe-/-Mir26b-/-, Apoe-/-LysMcreMir26bfl/fl 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, miR-26b mimic-loaded LNPs were injected in Apoe-/-Mir26b-/- 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. Results. Apoe-/-Mir26b-/- 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 miR-26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased in Apoe-/-Mir26b-/- mice. Moreover, Tgfb expression was increased by the miR-26b deficiency, leading to more hepatic fibrosis. A murine treatment model with miR-26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling upon miR-26b deficiency, which was rescued by LNP treatment. Finally, miR-26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices. Conclusions. Overall, our study demonstrates that the detrimental effects of miR-26b 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. ### Competing Interest Statement JJ is cofounder of AMICARE GmbH. The other authors declare no conflict of interest.