Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles

Lipid nanoparticles (LNPs) are clinically validated drug-delivery carriers. However, clinical data on intravenously administered LNPs are limited compared with those on intramuscularly administered LNPs (mRNA vaccines against COVID-19). Here, we reviewed three clinically tested intravenously administered LNPs (patisiran, mRNA-1944, and NTLA-2001). We summarize the differences and similarities in their formulations, mechanisms of action, and pharmacokinetics profiles. In humans, patisiran and mRNA-1944 exhibited similar multiphasic pharmacokinetic profiles with a secondary peak in the RNA concentration. siRNA (patisiran) and mRNA (mRNA-1944) exhibited prolonged blood circulation and were detectable for more than 28 days after a single administration. We further summarize the basics of extracellular vesicles (EVs) and discuss the potential linkages between LNPs and EVs. This Review provides an understanding of the human clinical data of intravenous LNP formulations, which can be potentially explored to develop next-generation LNP-and EV-based drug delivery carriers.