Tools for translation: non-viral materials for therapeutic mRNA delivery

In the citing paper

“To maximize translation, the mRNA sequence typically incorporates modified nucleosides, such as pseudouridine, N1-methylpseudouridine or other nucleoside analogues23.”

In the citing paper

“mRNA has shown therapeutic potential in a range of applications, including viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing2,4,7–17.”

In the citing paper

“These lipids can improve nanoparticle properties, such as particle stability, delivery efficacy, tolerability and biodistribution7,14,17.”

In the citing paper

“Trapped in endosomes, in which the pH is lower than in the extracellular environment, ionizable lipids are protonated and, therefore, become positively charged, which may promote membrane destabilization and facilitate endosomal escape of the nanoparticles7,11,14”

In the citing paper

“To function in vivo, lipid nanoparticle–mRNA formulations need to overcome multiple extracellular and intracellular barriers7,11 (Fig. 3a).”

In the citing paper

“In addition to cationic or ionizable lipids, lipid nanoparticle–mRNA formulations typically contain other lipid components, such as phospholipids (for example, phosphatidylcholine and phosphatidylethanolamine), cholesterol or polyethylene glycol (PEG)-functionalized lipids (PEG-lipids)7,14,17.”

In the citing paper

“The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo, because neutral lipids have less interactions with the anionic membranes of blood cells and, thus, improve the biocompatibility of lipid nanoparticles7,11,14.”

In the citing paper

“mRNA normally contains five structural elements, that is, a 5′ cap, a 3′ poly(A) tail, a protein-coding sequence and 5′ and 3′ untranslated regions (UTRs)2,4,7,13.”

In the citing paper

“These elements can be engineered to improve the stability and translational efficiency of mRNA2,4,7,13.”

In the citing paper

“Chemical modifications of specific IVT mRNA nucleotides, such as pseudouridine (ψ) and N1-methylpseudouridine (m1ψ), can reduce innate immune sensing of exogenous mRNA translation2,4,7,182.”

In the citing paper

“Chromatographic purification can remove double-stranded RNA, an analogue of viral genome, in IVT mRNA preparations, diminishing immune activation and increasing translational efficiency2,4,7,183.”

In the citing paper

“To address these concerns, the engineering of mRNA molecules (Box 1) and the design of lipid nanoparticles have been optimized2,4,7–17, which has contributed to the rapid development and clinical assessment15,17 of the two COVID-19 mRNA vaccines, mRNA-1273 (NCT04470427)19,20 and BNT162b2 (NCT04368728)21.”

In the citing paper

“Polymers, such as polyethyleneimine, protamine and polyaspartamide derivatives, are already widely used for mRNA delivery7–17.”

In the citing paper

“mRNA functions as the bridge between DNA and proteins in eukaryotic cells.[8, 12, 119]”

In the citing paper

“Polyethylenimine (PEI) is one of the most developed cationic polymers [39], but its toxicity has limited the therapeutic applications.[8, 124]”

In the citing paper

“Compared with protein drugs, mRNA can supplement both cytoplasmic and large transmembranic proteins.[8, 119, 120]”

In the citing paper

“Recently, many biomaterials have been developed for mRNA delivery, including lipids and lipid derived materials, polymers, and many others. [8, 39, 120, 124]”

In the citing paper

“Relative to plasmid DNA (pDNA), mRNA possesses temporary bioactivity and functions outside the nucleus, leading to a more controllable protein expression and avoiding the potential insertion of the genome.[8, 119, 120]”

In the citing paper

“For many GARDs, the liver is a preferred organ for mRNA-based PRTs because systemically administrated mRNA vehicles are predominantly trapped by the reticuloendothelial system (RES) in the liver.”

In the citing paper

“In addition, the interaction between apolipoprotein E (apoE) and biomaterials such as lipid and lipid derived materials facilitates the accumulation in the liver.[8, 18, 34, 39, 59, 120, 121, 124, 164, 165]”

In the citing paper

“Meanwhile, ionizable lipid and lipid derived materials, which acquire positive charges at low pH and become neutral at physiological pH, have been developed for decreasing the toxicity and immunogenicity while retaining the delivery efficiency.[8]”