De Anindita, Ko Young Tag
College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, South Korea.
Expert Opin Drug Deliv. 2023 Feb;20(2):175-187. doi: 10.1080/17425247.2023.2162876. Epub 2023 Jan 1.
Messenger ribonucleic acid (mRNA) and small interfering RNA (siRNA) are biological molecules that can be heated, frozen, lyophilized, precipitated, or re-suspended without degradation. Currently, ionizable lipid nanoparticles (LNPs) are a promising approach for mRNA therapy. However, the long-term shelf-life stability of mRNA-ionizable LNPs is one of the open questions about their use and safety. At an acidic pH, ionizable lipids shield anionic mRNA. However, the stability of mRNA under storage conditions remains a mystery. Moreover, ionizable LNPs excipients also cause instability during long-term storage.
This paper aims to illustrate why mRNA-ionizable LNPs have such a limited storage half-life. For the first time, we compile the tentative reasons for the short half-life and ultra-cold storage of mRNA-LNPs in the context of formulation excipients. The article also provided possible ways of prolonging the lifespan of mRNA-ionizable LNPs during long storage.
mRNA-ionizable LNPs are the future of genetic medicine. Current limitations of the formulation can be overcome by an advanced drying process or a whole new hybrid formulation strategy to extend the shelf life of mRNA-ionizable LNPs. A breakthrough technology may open up new research directions for producing thermostable and safe mRNA-ionizable LNPs at room temperature.
信使核糖核酸（mRNA）和小干扰RNA（siRNA）是生物分子，可进行加热、冷冻、冻干、沉淀或重悬而不降解。目前，可电离脂质纳米颗粒（LNPs）是mRNA治疗的一种有前景的方法。然而，mRNA-可电离LNPs的长期货架期稳定性是其使用和安全性方面的一个未解决问题。在酸性pH值下，可电离脂质会屏蔽带阴离子的mRNA。然而，mRNA在储存条件下的稳定性仍是一个谜。此外，可电离LNPs辅料在长期储存过程中也会导致不稳定性。
本文旨在阐明为什么mRNA-可电离LNPs的储存半衰期如此有限。我们首次在制剂辅料的背景下，梳理了mRNA-LNPs半衰期短和需要超低温储存的初步原因。本文还提供了在长期储存过程中延长mRNA-可电离LNPs寿命的可能方法。
mRNA-可电离LNPs是基因医学的未来。目前制剂的局限性可以通过先进的干燥工艺或全新的混合制剂策略来克服，以延长mRNA-可电离LNPs的货架期。一项突破性技术可能会为在室温下生产热稳定且安全的mRNA-可电离LNPs开辟新的研究方向。
