A2C18_D5 is an optimized lipid nanoparticle (LNP) component engineered with structural modifications to enhance mRNA delivery efficiency and safety. Its design incorporates a hydrophobic head group (A2, featuring a pentyl chain) and an unsaturated C18 tail, which collectively lower its pKa to the ideal range of 6–7, enabling stable encapsulation of nucleic acids and improved endosomal escape. In vitro and in vivo studies demonstrate that A2C18_D5 achieves mRNA delivery efficiency comparable to the clinically approved LNP benchmark MC3, while exhibiting over 200-fold higher potency than its precursor lipid (A1C11). The lipid’s reduced protonation capacity minimizes cytotoxicity and hemolytic risk, aligning with safety profiles of established LNPs. Upon intravenous administration, A2C18_D5 predominantly targets the liver and spleen, with a biodistribution profile favoring hepatic delivery. Its balanced combination of high transfection efficiency, low toxicity, and favorable pharmacokinetics positions A2C18_D5 as a promising candidate for next-generation mRNA therapeutics, including vaccines and treatments for liver-specific diseases. Further optimization of its head-tail structure highlights its versatility for tailored delivery applications.
