Lipid nanoparticle technology for therapeutic gene regulation in the liver

Abstract

Hereditary genetic disorders, cancer, and infectious diseases of the liver affect millions of people around the globe and are a major public health burden. Most contemporary treatments offer limited relief as they generally aim to alleviate disease symptoms. Targeting the root cause of diseases originating in the liver by regulating malfunctioning genes with nucleic acid-based drugs holds great promise as a therapeutic approach. However, employing nucleic acid therapeutics in vivo is challenging due to their unfavorable characteristics. Lipid nanoparticle (LNP) delivery technology is a revolutionary development that has enabled clinical translation of gene therapies. LNPs can deliver siRNA, mRNA, DNA, or gene-editing complexes, providing opportunities to treat hepatic diseases by silencing pathogenic genes, expressing therapeutic proteins, or correcting genetic defects. Here we discuss the state-of-the-art LNP technology for hepatic gene therapy including formulation design parameters, production methods, preclinical development and clinical translation.

Nanomaterial Delivery Systems for mRNA Vaccines

“…Increased branching is a common feature pursued by Acuitas, as Lipid A9 has a total of five branched chains [ 59 ] ( Table 2 ) vs. three for the Moderna LNPs. Increased branching is believed to create an ionizable lipid with a more cone-shaped structure, so that—when paired with the anionic phospholipid in the endosome—a greater membrane-disrupting ability will occur, following the molecular shape hypothesis outlined several decades ago [ 12 , 91 ]. When administered IV, Lipid 5 was not detectable in the liver at 24 h, while MC3 was present in the liver at 71% of its initial dose, verifying the degradability of Lipid 5.…”

“…There was no correlation of this increased potency with the LNP pKa, but there was a correlation with the absolute fluorescence of the TNS dye at pH 5, which indicates that the amplitude of protonation in the endosome correlates to mRNA expression, presumably by facilitating endosomal release. The additional carbon branch could also be expected to produce a more cone-shaped structure and thereby more membrane disruption according to the molecular shape hypothesis [ 12 , 91 ].…”

“…The purpose of this review is to overview the development of delivery systems for mRNA and then to summarize the preclinical and clinical findings of the SARS-CoV-2 mRNA vaccines and relate them to characteristics of the delivery system that contribute to their success. Several excellent reviews of mRNA delivery systems for vaccines and therapeutics that predate COVID-19 have been recently published [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Non-viral COVID-19 vaccine delivery systems

“…Once LNPs are internalized into cells, the acidic environment within endosomes could turn the surface charge of LNPs to positive, facilitating endosomal escape and mRNA release in the cytosol. As the critical component of LNPs, great efforts have been devoted to identify optimal ionizable lipids [ 24 , 25 ]. Representative ionizable lipids include: DLin-KC2-DMA [ 26 ] and DLin-MC3-DMA [ 27 ], which were based on rational design; C12-200 [ 28 ] and cKK-E12 [ 29 ], which were identified by high throughout screenings of large combinatorial libraries; L319 [ 30 ], TT3 [ 31 ], ssPalmE [ 32 ], Acuitas (A9) [ 33 ] and Moderna (L5) [ 34 ], which are biodegradable.…”

Alginate Nanoformulation: Influence of Process and Selected Variables

“…Nanomaterials have recently received much attention as drug carriers. In particular, nanoparticle-based nanoparticles [ 1 , 2 ], lipids [ 3 , 4 ], magnetic nanoparticles [ 5 , 6 ] and liposomes [ 7 ] have been widely studied in drug delivery systems. Among all, polymeric nanoparticles have been widely investigated due to their unique physicochemical properties [ 8 ].…”