The article reviews the design and clinical translation of lipid nanoparticles for mRNA delivery. Lipid nanoparticles have successfully entered clinical use for mRNA vaccines against COVID-19, marking a significant milestone in mRNA therapeutics. The review discusses the physiological barriers and administration routes for lipid nanoparticle–mRNA systems, emphasizing the importance of overcoming these barriers for effective delivery. Key considerations for clinical translation include good manufacturing practice, stability, storage, and safety. Preclinical and clinical studies of lipid nanoparticle–mRNA therapeutics for infectious diseases, cancer, and genetic disorders are highlighted, showcasing their potential in various therapeutic applications. The article also explores future possibilities and remaining challenges in this promising technology.The article reviews the design and clinical translation of lipid nanoparticles for mRNA delivery. Lipid nanoparticles have successfully entered clinical use for mRNA vaccines against COVID-19, marking a significant milestone in mRNA therapeutics. The review discusses the physiological barriers and administration routes for lipid nanoparticle–mRNA systems, emphasizing the importance of overcoming these barriers for effective delivery. Key considerations for clinical translation include good manufacturing practice, stability, storage, and safety. Preclinical and clinical studies of lipid nanoparticle–mRNA therapeutics for infectious diseases, cancer, and genetic disorders are highlighted, showcasing their potential in various therapeutic applications. The article also explores future possibilities and remaining challenges in this promising technology.