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

Abstract

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.

Optimizing Transfection Efficiency in CAR-T Cell Manufacturing through Multiple Administrations of Lipid-Based Nanoparticles

“…A central concern in lipofection pertains to the nanostructure characteristics of LNPs, as these features intricately influence the interactions with both plasma and endosomal membranes, thereby inducing substantial variations in gene release and, consequently, impacting TE. To elucidate this matter, we conducted synchrotron SAXS experiments.…”

Combination of miR159 Mimics and Irinotecan Utilizing Lipid Nanoparticles for Enhanced Treatment of Colorectal Cancer

“…The four components work together to optimize the pharmacokinetic profiles, distribution, and cellular uptake of drugs [ 35 ]. The in vivo behavior of LNPs is influenced by their physicochemical properties, including size, surface charge, and functional lipid groups [ 36 ]. These factors play a crucial role in determining the efficacy of drug delivery systems.…”

Mechanisms and Delivery of tRNA Therapeutics

“…Due to their high efficacy, previous clinical success, and ability to deliver pDNA as well as mRNA, LNPs show great promise in delivering therapeutic tRNA expression vectors. , As of now, the only LNP-based medicines that have reached the drug market have been RNA-based therapies, those being the two major mRNA-based COVID19 vaccines, Comirnaty and Spikevax, and Onpattro, a double stranded siRNA used to treat hereditary ATTR amyloidosis. , Considerable advantages to pDNA delivery over synthetic RNA delivery include longer-term expression, increased stability, and lower cost of synthesis. , LNPs have an advantage over viral vectors as they are less immunogenic and have improved safety. However, transfection efficiency of pDNA is poor in postmitotic cells, as LNPs do not contribute to nuclear import, while viral particles deliver DNA directly to the nucleus. − …”