Prevent and Reverse Metabolic Dysfunction-Associated Steatohepatitis and Hepatic Fibrosis via mRNA-Mediated Liver-Specific Antibody Therapy.

Chronic exposure of the liver to multiple insults culminates in the development of metabolic dysfunctionassociated steatohepatitis (MASH), a complicated metabolic syndrome characterized by hepatic steatosis and inflammation, typically accompanied by progressive fibrosis. Despite extensive clinical evaluation, there remain challenges in MASH drug development, which are primarily due to unsatisfactory efficacy and limited specificity. Strategies to address the unmet medical need for MASH with fibrosis before it reaches the irreversible stage of decompensated cirrhosis are critically needed. Herein, we developed an mRNA-mediated liver-specific antibody therapy for MASH and hepatic fibrosis using a targeted lipid nanoparticle (LNP) delivery system. When encapsulated with IL-11 single-chain variable fragment (scFv)-encoded mRNA, the targeted AA3G LNP (termed m@AA3G) specifically accumulated in the liver and secreted IL-11 scFv to neutralize overexpressed IL-11 in hepatic environments, thus inhibiting the IL-11 signaling pathway in hepatocytes and hepatic stellate cells. As a preventative regimen, systemic administration of m@AA3G reversed MASH and prevented the progression to fibrosis in a murine model of early MASH. Notably, m@AA3G exhibited superior efficacy compared to systemic administration of IL-11 scFv alone, attributed to the sustained antibody expression in the liver, which lasted 18-fold longer than that of IL-11 scFv. When tested in the MASH model with fibrosis, m@AA3G effectively ameliorated steatosis and resolved fibrosis and inflammation. These findings present a versatile LNP platform targeting liver cell subtypes for the sustained expression of therapeutic antibodies to treat MASH and fibrosis. The developed mRNA-mediated liver-specific antibody therapy offers a promising approach for addressing MASH and holds the potential for expansion to various other diseases.