Novel piperazine‐based ionizable lipid nanoparticles allow the repeated dose of mRNA to fibrotic lungs with improved potency and safety

mRNA-based protein replacement therapy has received much attention as a novel intervention in clinical disease treatment. Lipid nanoparticles (LNPs) are widely used for their therapeutic potential to efficiently deliver mRNA. However, translation been hampered by the immunogenicity of LNPs that may aggravate underlying states. Here, we report ionizable LNP with enhanced potency and safety. The piperazine-based biodegradable lipid (244cis) was developed formulation its level expression target tissue evaluated. It found 244cis enabled substantial (human erythropoietin), while it minimally induced secretion monocyte chemoattractant 1 (MCP-1) compared other conventional LNPs. Selective lung targeting further investigated tdTomato transgenic mice bleomycin-induced pulmonary fibrosis (PF). repeated administration Cre recombinase mRNA achieved complete transfection endothelial cells (~80%) over 40% Sca-1-positive fibroblasts. shown allows dose without loss activity due low immunogenicity. Our results demonstrate great treatment chronic diseases lungs improved