摘要
mRNA is a highly promising approach for disease prevention,yet its further application is currently limited by the low efficiency of delivery.Lipid nanoparticles(LNPs)are the mainstream delivery vehicles at present,and ionizable lipids,as a key component,have a particularly significant impact on delivery efficiency.To improve the efficiency of delivery,a library of ionizable lipids with tetra-branched hydrophobic tails was designed and synthesized by the Michael addition reaction.From this library,the lipid 10A was selected for the highest delivery efficiency.Further formulation screening yielded LNPs with excellent performance,which showed good efficacy in tumor prevention experiments.At the same time,the structure-activity relationship between the ionizable lipid structure and the delivery efficiency was elucidated.It was that the tetra-branched hydrophobic tails,as compared with the di-branched hydrophobic tails enhanced the stability of LNPs,provided uniformity of particle size and improved the efficiency of endocytosis and lysosomal escape,resulting in higher delivery efficiency.Meanwhile,tetra-branched lipids with hydroxyl groups in the head group performed even better.This research provides a theoretical basis and foundation for guiding the development of the next generation of ionizable lipids,and the developed 10A LNP also shows broad prospects for clinical translation.
基金
financially supported by the National Natural Science Foundation of China(No.T2293753)
the National Key R&D Program of China(No.2021YFA1201200)
the“Pioneer”and“Leading Goose”R&D Program of Zhejiang(No.022C03022)。
