Progress on nucleos(t)idyl lipid-based nanoparticles for nucleic acid drugs delivery.

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 <i>in vivo</i> delivery due to their negative charge, high molecular weight, and hydrophilicity. Lipid nanoparticles (LNPs) can encapsulate siRNA or mRNA through electrostatic interactions and five related drugs have been approved as of April 2025. However, due to the inevitable immunogenicity and hepatosplenic toxicity, most LNP-encapsulated nucleic acid drugs were terminated in the early clinical stage. Nucleos(t)idyl lipids are a class of amphiphilic molecules composed of nucleobases or nucleos(t)idyl 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 in delivery systems of nucleic acid drugs based on nucleos(t)idyl lipids and peptidyl lipids, and discuss their differences with LNP-encapsulated nucleic acid drugs, including structural characterization, molecular dynamics simulation, <i>in vivo</i> distribution, as well as efficacy and safety, so as to provide new ideas for improving the targeting delivery of nucleic acid drugs.