Paving the Road for RNA Therapeutics

Abstract

Therapeutic RNA molecules possess high potential for treating medical conditions if they can successfully reach the target cell upon administration. However, unmodified RNA molecules are rapidly degraded and cleared from the circulation. In addition, their large size and negative charge complicates their passing through the cell membrane. The difficulty of RNA therapy, therefore, lies in the efficient intracellular delivery of intact RNA molecules to the tissue of interest without inducing adverse effects. Here, we outline the recent developments in therapeutic RNA delivery and discuss the wide potential in manipulating the function of cells with RNAs. The focus is not only on the variety of delivery strategies but also on the versatile nature of RNA and its wide applicability. This wide applicability is especially interesting when considering the modular nature of nucleic acids. An optimal delivery vehicle, therefore, can facilitate numerous clinical applications of RNA.

Optimizing the Intracellular Delivery of Therapeutic Anti-inflammatory TNF-α siRNA to Activated Macrophages Using Lipidoid-Polymer Hybrid Nanoparticles

“…Although the ability of double-stranded RNA to mediate silencing of gene expression was discovered in Caenorhabditis elegans more than two decades ago (Elbashir et al, 2001 ), only four drugs based on siRNA have been approved to date, i.e., patisiran (Adams et al, 2018 ), givosiran (Balwani et al, 2020 ), lumasiran (McGregor et al, 2020 ), and inclisiran (Raal et al, 2020 ; Ray et al, 2020 ) used for systemic treatment of the polyneuropathy of hereditary transthyretin amyloidosis, acute hepatic porphyria, and elevated LDL cholesterol respectively. Major hurdles for unlocking of the full potential of siRNA for therapeutic applications are delivery-related challenges (Dammes and Peer, 2020 ). These include, but are not limited to, (i) protection of siRNA against degradation by exo- and endonucleases, (ii) cellular uptake, and (iii) endosomal escape and siRNA release in the cytosol after cellular internalization (Haussecker, 2014 ).…”

Resources, Production Scales and Time Required for Producing RNA Vaccines for the Global Pandemic Demand

“…The bottleneck for drug substance production is the formulation step, whereby the RNA is encapsulated into lipid nanoparticles (LNPs) using a controlled mixing process [ 8 , 35 ]. For this purpose, microfluidic mixing devices are commonly used to mix an aqueous stream containing the RNA with an ethanol stream containing the following four lipid components: phospholipids, polyethylene glycol (PEG) lipids, cholesterol and a proprietary ionisable lipid [ 35 , 36 , 37 , 38 , 39 , 40 ]. This bottleneck can be addressed by operating multiple microfluidic mixing devices in parallel or by using larger devices.…”

Self-assembled mRNA vaccines

“…As mentioned before, mRNA vaccines have gained significant interest in the last decade, with the current COVID-19 pandemic further fueling their development for mass use. The status of mRNA vaccines has recently been reviewed [ 2 , 159 , 284 ]. In this section, we focus on the development of clinically investigated mRNA vaccines against Coronavirus Disease 2019 (COVID-19) pandemic ( Table 1 ).…”