Lipid nanoparticles (LNPs) play an important role in mRNA vaccines against COVID-19. In addition, many preclinical and clinical studies, including the siRNA-LNP product, Onpattro®, highlight that LNPs unlock the potential of nucleic acid-based therapies and vaccines. To understand what is key to the success of LNPs, we need to understand the role of the building blocks that constitute them.

In this Review, we discuss what each lipid component adds to the LNP delivery platform in terms of size, structure, stability, apparent pK_a, nucleic acid encapsulation efficiency, cellular uptake, and endosomal escape. To explore this, we present findings from the liposome field as well as from landmark and recent articles in the LNP literature. We also discuss challenges and strategies related to in vitro/in vivo studies of LNPs based on fluorescence readouts, immunogenicity/reactogenicity, and LNP delivery beyond the liver. How these fundamental challenges are pursued, including what lipid components are added and combined, will likely determine the scope of LNP-based gene therapies and vaccines for treating various diseases.

脂质纳米颗粒 (LNP) 在针对 COVID-19 的 mRNA 疫苗中发挥重要作用。此外，许多临床前和临床研究，包括 siRNA-LNP 产品 Onpattro®，都强调 LNP 释放了基于核酸的疗法和疫苗的潜力。要了解什么是 LNP 成功的关键，我们需要了解构成它们的基石的作用。

在这篇综述中，我们讨论了每种脂质成分在大小、结构、稳定性、表观 pKa 、核酸包封效率、细胞摄取和内体逃逸方面对 LNP 递送平台_的贡献。为了探索这一点，我们展示了脂质体领域以及 LNP 文献中具有里程碑意义的最新文章的发现。我们还讨论了与基于荧光读数、免疫原性/反应原性和 LNP 肝外递送的 LNP 体外/体内研究相关的挑战和策略。如何应对这些基本挑战，包括添加和组合哪些脂质成分，将可能决定用于治疗各种疾病的基于 LNP 的基因疗法和疫苗的范围。