{Reference Type}: Journal Article
{Title}: Delivery of small interfering ribonucleic acid using lipid nanoparticles prepared with pH-responsive dipeptide-conjugated lipids.
{Author}: Matayoshi K;Song F;Koide H;Yonezawa S;Nitta C;Okada M;Ozaki N;Kurata M;Asai T;
{Journal}: Biochem Biophys Res Commun
{Volume}: 729
{Issue}: 0
{Year}: 2024 Oct 15
{Factor}: 3.322
{DOI}: 10.1016/j.bbrc.2024.150372
{Abstract}: The development of lipid nanoparticles (LNPs) has enabled the clinical application of small interfering ribonucleic acid (siRNA)-based therapies. Accordingly, various unique ionizable lipids have been explored for efficient siRNA delivery. However, safety concerns related to the structure of ionizable lipids have been raised. Here, we developed a pH-responsive dipeptide-conjugated lipid (DPL) for efficient, high safety siRNA delivery. We synthesized a DPL library by varying the dipeptide sequence and established a strong correlation between the knockdown efficiency of the DPL-based LNPs and the dipeptide sequence. The LNPs prepared with a DPL containing arginine (R) and glutamic acid (E) (DPL-ER) exhibited the highest knockdown efficiency. In addition, the DPL-ER-based LNPs with relatively long lipid tails (DPL-ER-C22:C22) exhibited a higher knockdown efficiency than those with short ones (DPL-ER-18:C18). The zeta potential of the DPL-ER-C22:C22-based LNPs increased as the pH decreased from 7.4 (physiological condition) to 5.5 (endosomal condition). Importantly, the DPL-ER-C22:C22-based LNPs exhibited a higher knockdown efficiency than the LNPs prepared using commercially available ionizable lipids. These results suggest that the DPL-based LNPs are safe and efficient siRNA delivery carriers.