ORS8-1542
Recognition-Element Engineering of Ionizable Lipids for Enhanced mRNA Vaccine Protection
Topic
S8. Frontiers of Functional Polymers in Biology and Medicine
When and Where
Oct 1, 2026
14:40 - 14:55
Room 108
Session Chairs
Mikyung SHIN
Jin YOO
Presenter(s)
Yoonkyung Kim (Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Co-Author(s)
Abstract
Ionizable lipids are key components of lipid nanoparticles (LNPs) that govern the delivery and biological performance of mRNA vaccines. Despite extensive efforts to improve transfection efficiency, the influence of ionizable lipid structure on vaccine protection remains poorly understood. Here, we report a series of rationally designed ionizable lipids bearing head groups inspired by Dervan's polyamide nucleic acid binders, including imidazole- and pyrrole-carboxamide motifs and their isosteric analogues. Systematic modulation of these directional polar protic recognition elements generated LNPs with distinct physicochemical and biological properties, revealing that even subtle structural variations, including regioisomerism, profoundly influence mRNA delivery and vaccine efficacy. Our lead lipid 11 mediated rapid and enhanced intramuscular protein expression, achieving 4.4- and 2.0-fold higher expression than the benchmark lipid SM-102 at 1 and 3 h post-injection, respectively, with no detectable liver expression. When formulated with SARS-CoV-2 spike mRNA, these LNPs elicited robust humoral and cellular immune responses. Notably, lipid 13 conferred markedly superior antiviral protection in an hACE2 transgenic mouse challenge model, reducing pulmonary viral RNA to near-baseline levels while maintaining body weight and complete survival despite inducing substantially lower anti-spike receptor-binding domain (RBD) IgG titers than SM-102. Preliminary studies further demonstrated neutralizing activity of the LNP with lipid 13 against multiple SARS-CoV-2 variants. Collectively, these findings demonstrate that precise installation of molecular recognition elements within ionizable lipid head groups can profoundly influence mRNA vaccine performance and antiviral protection, establishing head-group engineering as a promising molecular design strategy for next-generation mRNA delivery systems.
