Enhancing mRNA Delivery through the Modification of Lipid Nanoparticles with Cholesterol Derivatives
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초록
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Recently, mRNA-based therapeutics have gained significant attention in the field of gene therapy for treating various diseases. Lipid nanoparticles (LNPs) have emerged as promising vehicles for packaging and delivering mRNA with low immunogenicity. However, while mRNA delivery has several advantages, the delivery efficiency and stability of LNPs remain challenging for mRNA therapy. The study focuses on a novel ionizable cholesterol analog, 3β[L-histidinamide-carbamoyl] cholesterol (Hchol), which is integrated into LNPs to improve their potency in delivering mRNA. This study demonstrates that incorporating Hchol into LNPs enhances their pKa values, facilitating endosomal escape of mRNA, which is critical for effective intracellular delivery. In both in vitro and in vivo experiments, Hchol-LNPs showed improved mRNA delivery efficiency, leading to robust protein expression. Notably, the Hchol-LNPs also exhibited lower immunogenicity and maintained stability over time.