The evolution of ionizable Lipid nanoparticle components used for development of vaccines and gene Therapy: a review

Aim and Background: Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nano-delivery system for therapeutic nucleic acids. One main factor in designing of lipids for nucleic acids delivery is to overcome the endosomal barriers for efficient intracellular delivery. LNPs typically consist of four components: ionizable lipid, phospholipids, cholesterol, and PEGylated lipid. We performed review of proposed new approaches for the evolution of LNP components for efficient intracellular delivery. Methods: In order to finding available articles on preparation of lipid nanoparticles for vaccines and gene therapy, we searched the key considerations for developing an LNP system and also the structure and function evolution of lipids used for efficient intracellular delivery of different therapeutic nucleic acids. A search in two databases, PubMed, and Google scholar was conducted from January, 2019 to march, 2023 with the key words: ionizable lipid nanoparticles, lipid nanoparticles, LNP formulation and RNA delivery. Results and discussion: The evolution of structure and function of lipids as well as their LNP formulation from the first generation cationic lipids to multifunctional ionizable LNPs have been discussed. The formulations used to develop FDA-approved LNP based Covid-19 vaccines was also compared to other LNP formulations. Systematic categorization of these lipids based on their structures is presented and the role of structure, stability and apparent pKa is also discussed. Conclusion: The choice of proper lipids has shown to play a predominant role for the efficient intracellular nucleic acid delivery through LNPs.