Prevent\nand Reverse Metabolic Dysfunction-Associated\nSteatohepatitis and Hepatic Fibrosis via mRNA-Mediated Liver-Specific\nAntibody Therapy

Chronic\nexposure of the liver to multiple insults culminates in\nthe development of metabolic dysfunction<b>-</b>associated steatohepatitis\n(MASH), a complicated metabolic syndrome characterized by hepatic\nsteatosis and inflammation, typically accompanied by progressive fibrosis.\nDespite extensive clinical evaluation, there remain challenges in\nMASH drug development, which are primarily due to unsatisfactory efficacy\nand limited specificity. Strategies to address the unmet medical need\nfor MASH with fibrosis before it reaches the irreversible stage of\ndecompensated cirrhosis are critically needed. Herein, we developed\nan mRNA-mediated liver-specific antibody therapy for MASH and hepatic\nfibrosis using a targeted lipid nanoparticle (LNP) delivery system.\nWhen encapsulated with IL-11 single-chain variable fragment (scFv)-encoded\nmRNA, the targeted AA3G LNP (termed m<i>IL11-scFv</i>@AA3G)\nspecifically accumulated in the liver and secreted IL-11 scFv to neutralize\noverexpressed IL-11 in hepatic environments, thus inhibiting the IL-11\nsignaling pathway in hepatocytes and hepatic stellate cells. As a\npreventative regimen, systemic administration of m<i>IL11-scFv</i>@AA3G reversed MASH and prevented the progression to fibrosis in\na murine model of early MASH. Notably, m<i>IL11-scFv</i>@AA3G exhibited superior efficacy compared to systemic administration\nof IL-11 scFv alone, attributed to the sustained antibody expression\nin the liver, which lasted 18-fold longer than that of IL-11 scFv.\nWhen tested in the MASH model with fibrosis, m<i>IL11-scFv</i>@AA3G effectively ameliorated steatosis and resolved fibrosis and\ninflammation. These findings present a versatile LNP platform targeting\nliver cell subtypes for the sustained expression of therapeutic antibodies\nto treat MASH and fibrosis. The developed mRNA-mediated liver-specific\nantibody therapy offers a promising approach for addressing MASH and\nholds the potential for expansion to various other diseases.