Which Lipid Nanoparticle (LNP) Designs Work? A Simple Kinetic Model Linking LNP Chemical Structure to In Vivo Delivery Performance

Although lipid nanoparticles (LNPs) are the predominant nanocarriers for short-interfering RNA (siRNA) delivery, most therapies use nearly identical formulations that have taken 30 years to design but lack the diverse property ranges necessary for versatile application. This dearth in variety and the extended timeline for implementation are attributed to a limited understanding of how LNP properties facilitate overcoming biological barriers. Herein, a simple kinetic model was developed by using major rate-limiting steps for siRNA delivery, and this model enabled the identification of a critical parameter to predict LNP efficacy without extensive experimental testing. A volume-averaged log D, the "solubility" of charged molecules as a function of pH weighted by component volume fractions, resulted in a good correlation between LNP composition and siRNA delivery. Both the effects of modifying the structures of ionizable lipids and LNP composition on gene silencing were easily captured in the model predictions. Thus, this approach provides a robust LNP structure–activity relationship to dramatically accelerate the realization of effective LNP formulations.