关键词: 核酸药物, 核苷(酸)脂材, 脂质纳米粒, 体内递送

Abstract: Nucleic acid drugs can function at the gene level, and have the advantages of simple synthesis, easy modification and high specificity. However, there are many obstacles in transfection and in vivo delivery due to their negative charge, high molecular weight, and hydrophilicity. Lipid nanoparticles (LNPs) can encapsulate siRNA or mRNA through electrostatic interactions and four related drugs have been approved. However, due to the inevitable immunogenicity and hepatosplenic toxicity, most LNP-encapsulated nucleic acid drugs were terminated in the early clinical stage. Nucleos(t)lipids are a class of amphiphilic molecules composed of bases or nucleos(t)heads, linkers and lipid tail chains, which can bind with the bases of nucleic acid drugs through hydrogen bonding and π-π stacking and self-assemble to form nanoparticles or micelles with broad application prospects. In this review, we summarize the research progress of nucleos(t)lipid-based nucleic acid drug delivery systems, and discuss the differences between nucleos(t)lipids and LNP-encapsulated nucleic acid drugs from the aspects of structural characterization, molecular dynamics simulation, in vivo distribution, as well as efficacy and safety, so as new ideas for improving the targeting delivery of nucleic acid drugs.

Key words: nucleic acid drugs, nucleos(t)idyl lipids, lipid nanoparticles, in vivo delivery