A33-D268 is an ionizable lipid derived from a 2-aminoimidazole (AM) core, featuring an asymmetric hydrophobic tail structure designed to optimize mRNA interactions. Selected as the top candidate from a 21-lipid library through molecular dynamics (MD) simulations, it demonstrated superior performance: low root mean square deviation (RMSD) and the smallest radius of gyration (Rg), indicating tight mRNA compaction, alongside moderate electrostatic energy and above-average hydrogen bonding for stable encapsulation. Formulated into LNPs, it achieves efficient muscle-specific transfection post-intramuscular injection, rivaling commercial ALC-0315 LNPs. Crucially, it exhibits 29-fold lower hepatic off-target expression, attributed to its inability to leverage serum protein coronas for liver tropism.
