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

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.

Delineating effect of cationic head group and preparation method on transfection versus toxicity of lipid-based nanoparticles for gene delivery

“…In terms of formulation components, cationic or ionizable complexing lipid or surfactant stands out to be the most critical component in aspect of complexing negatively charged nucleic acid as well as mediating its endosomal escape. It is a well-established fact that cationic or ionizable lipid can facilitate electrostatic interaction between lipid nanocarriers as well as the cellular or endosomal membranes, to enable both cellular uptake and endosomal release of gene cargos (7). More speci cally, in case of DNA, it needs to be translocated to the nucleus of the cells following endosomal escape to achieve target protein expression.…”

“…Chemical structure of cationic lipids like DOTAP (N-[1-(2,3dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl) and DOTMA (N-[1-(2,3-dioleyloxy)propyl]-N,N,Ntrimethylammonium chloride) consist of quaternary amine groups that contribute to their high positive charge to condense and encapsulate negatively charged pDNA in liposomal formulations for intracellular delivery. Even though these quaternary ammonium lipids result in high transfection e ciency, they are found to be toxic rendering them incompatible for in vivo administration (7,8). To overcome this challenge, arginine-based cationic surfactants including lauroyl arginine ethyl ester (LAE) and arginine-N-lauroyl amide dihydrochloride (ALA) were also explored by various researchers to develop cationic liposomes for charge mediated pDNA complexation and subsequent transfection in target cells in vitro (9,10).…”

A Perspective of Engineered Lipids and Liposomes: Chemical Design and Functional Application Based on Therapeutic Safety

“…The amino group is positively charged upon protonation under the environment with a pH lower than 4.0 and can be combined with negatively charged genes to achieve effective payload, while also aiding in their escape from endosomes and lysosomes. 47 Ionizable lipids have been developed as siRNA and mRNA delivery systems with high transfection efficiency and safety. 47 Anionic lipids are common in both eukaryotic and prokaryotic cell membranes.…”

MicroRNA-nanoparticles against cancer: Opportunities and challenges for personalized medicine

“… 76 The first generation of NP-based therapy included lipid systems such as liposomes, micelles, and dendrimers containing inorganic gold or magnetic NPs used as biomarkers for their peculiar surface properties. 77 NPs have peculiar properties such as a large surface and porosity, which allow encapsulating larger drug dosages and contributing to an easier targeting to cancer sites. According to the features of the tumor microenvironment, the drug release may be mediated by internal stimuli as alteration in temperature, pH, ionic strength, redox state, or by enzymatic action or by external stimuli, as electric and electromagnetic fields, radiation, or ultrasounds.…”