Looking Back, Moving Forward: Lipid Nanoparticles as a Promising Frontier in Gene Delivery

Lipid nanoparticles (LNPs) have shown remarkable success in delivering genetic materials like COVID-19 LNP vaccines, such as mRNA-1273/SpikeVax by Moderna and BNT162b2/Comirnaty by BioNTech/Pfizer, as well as siRNA for rare inherited diseases, such as Onpattro from Alnylam Pharmaceuticals. These LNPs are advantageous since they minimize side effects, target specific cells, and regulate payload delivery. There has been a surge of interest in these particles due to their success stories; however, we still do not know much about how they work. This perspective will recapitulate the evolution of lipid-based gene delivery, starting with Felgner's pioneering 1987 PNAS paper, which introduced the initial DNA-transfection method utilizing a synthetic cationic lipid. Our journey takes us to the early 2020s, a time when advancements in bionano interactions enabled us to create biomimetic lipoplexes characterized by a remarkable ability to evade capture by immune cells in vivo. Through this overview, we propose leveraging previous achievements to assist us in formulating improved research goals when optimizing LNPs for medical conditions such as infectious diseases, cancer, and heritable disorders.