Wang Chenglong, Zhou Yiming, Gao Yanxia, Pan Xinping, Jia William, Wu Tengjie, Zhang Yuntao
CNBG-Virogin Biotech (Shanghai) Co., Ltd., Shanghai 201800, China.
Shanghai-Virogin Biotech Co., Ltd., Shanghai 201800, China.
ACS Appl Mater Interfaces. 2025 Jun 18. doi: 10.1021/acsami.5c08444.
mRNA offers a promising therapeutic approach for gene therapy, cancer treatment, and vaccine development. Lipid nanoparticles (LNPs) have emerged as a primary delivery system for mRNA. Ionizable lipids are key components of LNPs. Given the current limitations of LNPs regarding efficacy, safety, and stability, we undertook this research. We synthesized 11 asymmetric sterol-conjugated ionizable lipids. These lipids and their resulting LNP formulations were screened. Five of these ionizable lipids were selected, and a 40-50% molar ratio was determined to be optimal for the LNP formulation. Luciferase mRNA-loaded LNPs formulated with sterol-conjugated ionizable lipids demonstrated luminescence comparable to that of commercial LNPs composed of ALC-0315 and prolonged protein expression in mice. Furthermore, accelerated stability studies demonstrated that LNPs exhibited good stability. Additionally, LNPs loaded with varicella-zoster virus (VZV) gE mRNA successfully induced both humoral- and T-cell-mediated immune responses. Finally, safety studies revealed that LNPs based on these ionizable lipids exhibited improved safety profiles compared with commercially available LNPs. In conclusion, these sterol-conjugated ionizable lipid nanoparticles enable prolonged and safe mRNA delivery, representing a significant advance in mRNA delivery technology.
信使核糖核酸（mRNA）为基因治疗、癌症治疗和疫苗开发提供了一种很有前景的治疗方法。脂质纳米颗粒（LNP）已成为mRNA的主要递送系统。可电离脂质是LNP的关键成分。鉴于LNP目前在疗效、安全性和稳定性方面的局限性，我们开展了这项研究。我们合成了11种不对称的甾醇共轭可电离脂质。对这些脂质及其形成的LNP制剂进行了筛选。从中选择了5种可电离脂质，并确定40-50%的摩尔比对于LNP制剂是最佳的。用甾醇共轭可电离脂质配制的载有荧光素酶mRNA的LNP在小鼠体内表现出与由ALC-0315组成的商业LNP相当的发光效果，并延长了蛋白质表达。此外，加速稳定性研究表明LNP具有良好的稳定性。此外，载有水痘带状疱疹病毒（VZV）gE mRNA的LNP成功诱导了体液免疫和T细胞介导的免疫反应。最后，安全性研究表明，与市售LNP相比，基于这些可电离脂质的LNP具有更好的安全性。总之，这些甾醇共轭可电离脂质纳米颗粒能够实现延长且安全的mRNA递送，代表了mRNA递送技术的重大进步。
