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.
摘要：
脂质纳米颗粒（LNP）的开发使得基于小干扰核糖核酸（siRNA）的疗法能够临床应用。因此，已经探索了各种独特的可电离脂质用于有效的siRNA递送。然而,与可电离脂质结构相关的安全问题已经被提出。这里,我们开发了一种pH响应性二肽偶联脂质（DPL），高安全性的siRNA输送。我们通过改变二肽序列合成了DPL文库,并在基于DPL的LNP的敲低效率和二肽序列之间建立了强相关性。用含有精氨酸(R)和谷氨酸(E)(DPL-ER)的DPL制备的LNP表现出最高的敲低效率。此外,具有相对较长脂质尾的基于DPL-ER的LNP（DPL-ER-C22：C22）比具有较短脂质尾的LNP（DPL-ER-18：C18）表现出更高的敲低效率。基于DPL-ER-C22:C22的LNP的ζ电位随着pH从7.4(生理条件)降低至5.5(内体条件)而增加。重要的是,基于DPL-ER-C22:C22的LNP表现出比使用市售可电离脂质制备的LNP更高的敲低效率。这些结果表明基于DPL的LNP是安全且有效的siRNA递送载体。
