The liver is a vital organ that functions to detoxify the body. Liver cancer and infectious diseases such as influenza and malaria can fatally compromise liver function. mRNA delivery is a relatively new means of therapeutic treatment which enables expression of tumor or pathogenic antigens, and elicits immune responses for therapeutic or prophylactic effect. Novel nanoparticles with unique biological properties serving as mRNA carriers have allowed mRNA-based therapeutics to become more clinically viable and relevant. In this review, we highlight recent progress in development of nanoparticle-based mRNA delivery systems for treatment of various liver diseases. First, we present developments in nanoparticle systems used to deliver mRNAs, with specific focus on enhanced cellular uptake and endosomal escape achieved through the use of these nanoparticles. To provide context for diseases that target the liver, we provide an overview of the function and structure of the liver, as well as the role of the immune system in the liver. Then, mRNA-based therapeutic approaches for addressing HCC are highlighted. We also discuss nanoparticle-based mRNA vaccines for treating hepatotropic infectious diseases. Finally, we present current challenges in the clinical translation of nanoparticle-based mRNA delivery systems and provide outlooks for their utilization in treating liver-related diseases.