Structure and Function of Cationic and Ionizable Lipids for Nucleic Acid Delivery

Sun, D; Lu, ZR

Abstract

Hereditary genetic diseases, cancer, and infectious diseases are affecting global health and become major health issues, but the treatment development remains challenging. Gene therapies using DNA plasmid, RNAi, miRNA, mRNA, and gene editing hold great promise. Lipid nanoparticle (LNP) delivery technology has been a revolutionary development, which has been granted for clinical applications, including mRNA vaccines against SARS-CoV-2 infections. Due to the success of LNP systems, understanding the structure, formulation, and function relationship of the lipid components in LNP systems is crucial for design more effective LNP. Here, we highlight the key considerations for developing an LNP system. The evolution of structure and function of lipids as well as their LNP formulation from the early-stage simple formulations to multi-components LNP and multifunctional ionizable lipids have been discussed. The flexibility and platform nature of LNP enable efficient intracellular delivery of a variety of therapeutic nucleic acids and provide many novel treatment options for the diseases that are previously untreatable.

Keywords: cationic lipid; ionizable lipid; lipid nucleic acid nanoparticles; nucleic acid delivery; structural effect

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Liposomes for DNA/RNA Delivery

Cationic lipids and ionizable lipids are two types of lipid molecules commonly used for nucleic acid delivery. They play an important role in nucleic acid delivery, effectively guiding DNA and RNA into cells, and are therefore widely used in gene therapy and research. Cationic lipids have positively charged head groups that can interact with negatively charged phosphate groups in DNA or RNA to form lipid-nucleic acid complexes that can be efficiently entered through endocytosis. cells and release nucleic acids into the cytoplasm, often used for applications such as gene delivery and siRNA (small interfering RNA) delivery. Ionizable lipids have a pKa (acid dissociation constant) value, which means they can ionize into charged molecules within a specific pH range. This ionization property can help ionizable lipids adapt more effectively to different environments within cells. In nucleic acid delivery, cationic lipids or ionizable lipids are typically mixed with nucleic acids to form liposome-nucleic acid complexes, which are then directed into target cells.

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