Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Adv Drug Deliv Rev. 2024 Nov;214:115446. doi: 10.1016/j.addr.2024.115446. Epub 2024 Sep 16.
In the past decade, nucleic acid therapies have seen a boon in development and clinical translation largely due to advances in nanotechnology that have enabled their safe and targeted delivery. Nanoparticles can protect nucleic acids from degradation by serum enzymes and can facilitate entry into cells. Still, achieving endosomal escape to allow nucleic acids to enter the cytoplasm has remained a significant barrier, where less than 5% of nanoparticles within the endo-lysosomal pathway are able to transfer their cargo to the cytosol. Lipid-based drug delivery vehicles, particularly lipid nanoparticles (LNPs), have been optimized to achieve potent endosomal escape, and thus have been the vector of choice in the clinic as demonstrated by their utilization in the COVID-19 mRNA vaccines. The success of LNPs is in large part due to the rational design of lipids that can specifically overcome endosomal barriers. In this review, we chart the evolution of lipid structure from cationic lipids to ionizable lipids, focusing on structure-function relationships, with a focus on how they relate to endosomal escape. Additionally, we examine recent advancements in ionizable lipid structure as well as discuss the future of lipid design.
在过去的十年中，由于纳米技术的进步，核酸疗法在开发和临床转化方面取得了蓬勃发展，使它们能够安全且靶向地递送到体内。纳米颗粒可以保护核酸免受血清酶的降解，并促进其进入细胞。然而，实现内涵体逃逸以允许核酸进入细胞质仍然是一个重大的障碍，在内涵体-溶酶体途径中，只有不到 5%的纳米颗粒能够将其货物转移到细胞质中。基于脂质的药物递送载体，特别是脂质纳米颗粒（LNPs），已经过优化以实现有效的内涵体逃逸，因此已被临床选为首选载体，这在其在 COVID-19 mRNA 疫苗中的应用中得到了证明。LNPs 的成功在很大程度上归因于可以特异性克服内涵体障碍的脂质的合理设计。在这篇综述中，我们绘制了从阳离子脂质到可离子化脂质的脂质结构演变图，重点关注结构-功能关系，并特别关注它们与内涵体逃逸的关系。此外，我们还研究了可离子化脂质结构的最新进展，并讨论了脂质设计的未来。
