A central challenge in nucleic acid therapeutics is how to deliver genetic cargo efficiently while avoiding immunotoxicity that limits clinical translation. Lipid nanoparticles (LNPs) are effective delivery systems for mRNA and DNA. However, the positive charges of their ionizable lipids, which are required for endosomal escape, also cause immunostimulatory effects.
Our lab develops next-generation lipid nanoparticle systems that decouple delivery efficiency from immunostimulation. We have designed a new class of ionizable lipids termed S lipids. These lipids are negatively charged at physiological pH 7.4 and become positively charged in the acidic endosomal environment, enabling efficient nucleic acid encapsulation and endosomal release. This charge switching behavior enables the formation of lipid nanoparticles (termed SNPs) that retain high delivery efficiency while minimizing immunostimulatory effects.