Nano–Bio Interactions: Exploring the Biological Behavior and the Fate of Lipid-Based Gene Delivery Systems

Gene therapy for many diseases is rapidly becoming a reality, as demonstrated by the recent approval of various nucleic acid-based therapeutics. Non-viral systems such as lipid-based carriers, lipid nanoparticles (LNPs), for delivering different payloads including small interfering RNA, plasmid DNA, and messenger RNA have been particularly extensively explored and developed for clinical uses. One of the most important issues in LNP development is delivery to extrahepatic tissues. To achieve this, various lipids and lipid-like materials are being examined and screened. Several LNP formulations that target extrahepatic tissues, such as the spleen and the lungs have been developed by adjusting the lipid compositions of LNPs. However, mechanistic details of how the characteristics of LNPs affect delivery efficiency remains unclear. The purpose of this review is to provide an overview of LNP-based nucleic acid delivery focusing on LNP components and their structures, as well as discussing biological factors, such as biomolecular corona and cellular responses related to the delivery efficiency.