Abstract
Farnesoid X receptor (FXR) regulates hepatic lipid metabolism and is a promising target for metabolic dysfunction-associated steatotic liver disease (MASLD), yet the efficacy and tolerability of FXR agonists may be influenced by their dose and tissue distribution. Thus, this study aimed to evaluate the therapeutic efficacy of FXR-encoding mRNA encapsulated in LNPs combined with a low dose of FXR agonist GW4064 in MASLD in vitro and in vivo. LNPs demonstrated superior delivery efficiency over PEI and Lipofectamine 3000 in hepatocytes and achieved rapid, liver-specific accumulation in mice. While FXR mRNA-LNP alone elevated hepatic FXR expression without spontaneous activation, its combination with low-dose GW4064 enhanced FXR pathway activity. In diet-induced MASLD mice, this combination therapy significantly reduced hepatic lipid accumulation and improved liver histology compared to individual treatments. Our findings indicate that combining FXR mRNA-LNP with low-dose GW4064 effectively alleviates fatty liver, offering a novel FXR-based strategy for MASLD.