Introduction: Ionizable lipids are critical components in lipid nanoparticles. These molecules sequester nucleic acids for delivery to cells. However, to build more efficacious delivery molecules, the field must continue to broaden structure-function studies for greater insight. While nucleic acid-binding efficiency, degradability and nanoparticle stability are vitally important, this review offers perspective on additional factors that must be addressed to improve delivery efficiency.
Areas covered: We discuss how administration route, cellular heterogeneity, uptake pathway, endosomal escape timing, age, sex, and threshold effects can change depending on the type of LNP ionizable lipid.
Expert opinion: Ionizable lipid structure-function studies often focus on the efficiency of RNA utilization and biodistribution. While these focus areas are critical, they remain high-level observations. As our tools for observation and system interrogation improve, we believe that the field should begin collecting additional data. At the cellular level, this data should include age (dividing or senescent cells), sex and phenotype, cell entry pathway, and endosome type. Additionally, administration route and dose are essential to track. This additional data will allow us to identify and understand heterogeneity in LNP efficacy across patient populations, which will help us provide better ionizable lipid options for different groups.
Keywords: Ionizable lipid; LNP; RNA; endosomal escape; functional delivery; lipid nanoparticle; patient stratification; ribonucleic acid; structure–function; uptake mechanism.