The role of excipients in lipid nanoparticle metabolism: implications for enhanced therapeutic effect

Lipid nanoparticles (LNPs) are multicomponent delivery vehicles for nucleic acids that are generally comprised of ionizable lipids, phospholipids, cholesterol and lipid-poly(ethylene glycol) molecules. It is well established that both the composition and relative amounts of each component significantly impact the efficiency of nucleic acid delivery by LNPs, as well as their organ-specific targeting. However, the post-delivery fate of every component is less discussed such as the degradation, clearance, and retention in the body. The longevity and metabolites of each component can greatly influence overall tolerability and safety. For instance, slowly degrading ionizable lipids, which comprise around 50% of the LNP, have been shown to illicit an extended inflammatory response. In this review significant importance is placed on chemistries that improve the tolerability and safety of certain LNP components, such as molecular modifications to ionizable lipids, lipid-poly(ethylene glycol) and nucleic acids. Additionally, we discuss how formulation strategies, such as the amount of cholesterol and phospholipids added to optimize clearance, can enhance biodegradability and reduce inflammation. Furthermore, this review will provide an understanding of the considerations around designing LNP components for better or more predictable metabolism such modified nucleic acids and biodegradable chemical linkers in ionizable lipids.