The evolution of lipid nanoparticles: Paving the way for next-generation nucleic acid medicines

Nucleic acid-based therapies have emerged as promising strategies for the regulation of gene expression and the production of therapeutic antigens or proteins for a series of diseases, including cancers, rare diseases, and infectious diseases. However, their clinical application faces challenges. These include high molecular weight, limited cellular uptake, and susceptibility to enzymatic degradation by nucleases in vivo. Both viral and non-viral delivery vectors have been developed as a means of addressing these limitations, including lipid nanoparticles (LNPs), exosomes, polymers, and inorganic nanoparticles. Among these, LNPs have garnered significant attention due to their superior biocompatibility, high delivery efficiency and customizable design potential, as demonstrated by the clinical success of the FDA-approved siRNA drug Onpattro®. The critical role of nucleic acid drug carriers is discussed in this review. It also outlines the major types of carriers under development and examines the advancements and applications in LNP-based systems for nucleic acid delivery. By conducting a review of recent advancements in LNP design, delivery mechanisms, and clinical applications, this article aims to clarify the ways in which LNPs overcome delivery barriers, compare LNPs with other carriers, and identify key trends that can inform the development of next-generation LNP platforms for nucleic acid therapeutics.