A tale of nucleic acid-ionizable lipid nanoparticles: Design and manufacturing technology and advancement.

ABSTRACT Introduction Ionizable lipid nanoparticles (LNPs) have been proven to have high encapsulation, cellular uptake, and effective endosomal escape and are therefore promising for nucleic acid delivery. The combination of ionizable lipids, helper lipids, cholesterol, and PEG lipids advances nucleic acid-ionizable LNPs and distinguishes them from liposomes, SLNs, NLCs, and other lipid particles. Solvent injection and microfluidics technology are the primary manufacturing techniques for commercialized ionizable LNPs. Microfluidics technology limitations restrict the rapid industrial scale-up and therapeutic effectiveness of ionized LNPs. Alternative manufacturing technologies and target-specific lipids are urgently needed. Area covered This article provides an in-depth update on the lipid compositions, clinical trials, and manufacturing technologies for nucleic acid-ionizable LNPs. For the first time, we updated the distinction between ionizable LNPs and other lipid particles. We also proposed an alternate thermocycling technology for high industrial scale-up and the stability of nucleic acid-ionizing LNPs. Expert opinion Nucleic acid-ionizable LNPs have a promising future for delivering nucleic acids in a target-specific manner. Though ionizing LNPs are in their early stages, they face several challenges, including only hepatic delivery, a short shelf life, and ultra-cold storage. In our opinion, ligand-based, target-specific synthesized novel lipids and advanced manufacturing technologies can easily overcome the restrictions and open up a new approach for improved therapeutic efficacy for chronic disorders. Graphical abstract