Recent Advances in RNA Therapeutics and RNA Delivery Systems Based on Nanoparticles

Abstract

Recently, there have been significant advances in the field of RNA‐based therapeutics harnessing exogenous RNAs including small interfering RNA (siRNA), microRNA (miRNA) mimics, and in vitro transcribed (IVT) mRNAs. RNA‐based therapeutics are one of the most attractive classes of drugs for treating a variety of diseases. In principle, RNA‐based therapeutics offer numerous advantages compared to the conventional small‐molecule‐based therapies. However, there are several drawbacks to overcome in the application of RNA‐based therapeutics, including the instability of RNAs and presence of various biological barriers. In the past decades, there have been various attempts to overcome these key challenges. Here, the authors present an overview of RNA‐based therapeutics and recent advances including their delivery systems and clinical applications. In addition, the current challenges of RNA‐based drugs are discussed, followed by perspectives with regard to the development of these promising drug candidates to elicit successful clinical outcomes.

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

“…AGO is strongly downregulated in melanoma and re-expression could represent a therapeutic option [275,276]. The inhibitory effect of tumor-specific miRNAs on their target mRNAs could be inhibited by sequestering the miRNAs using, for example, lncRNAs as competing endogenous RNAs (ceRNAs) [277][278][279], by small-molecule inhibitors [280] or modified oligoribonucleotides (e.g., LNAs) [281]. Those can be specifically delivered into tumor cells using a nanoparticle based system [282].…”

“…The problem with such miRNA mimics or anti-miRs, respectively, which consist of naturally occurring RNA components, is that they have an only low binding affinity and show poor resistance against intracellular nucleases and degradation [309]. For therapeutic use, it is better to use chemically modified RNA molecules, for example, locked nucleic acids (LNAs) [281] (Figure 9). LNAs comprise an extremely high affinity to their targets, a high sensitivity regarding mismatches and a good stability [309].…”

“…Nanoparticles are between 1-100 nm in diameter. They can be built using positively charged lipids surrounding the RNA as well as positive-charged polymers or silica, which can be equipped with small pores, where drugs assisting delivery and RNase protection can be attached [281]. The first siRNA-based drug successfully tested in a Phase I clinical study against solid tumors (the study was investigating melanoma patients) using a nanoparticle-based delivery system was CALAA-01 [261].…”

“…In the described clinical study of CALAA-01, the first siRNA-based drug successfully tested in a Phase I clinical trial, delivery to melanoma cells worked specific and without severe side effects [331]. However, there are open questions regarding stability of the respective particles, endosomal escape for miRNA delivery, biodegradability after miRNA release or the risk of accumulation in the human body [281].…”

Enlisting the mRNA Vaccine Platform to Combat Parasitic Infections

“…Other recent reviews on the mRNA vaccine platform have given a comprehensive and complete overview of current mRNA delivery and transfection systems [43,46]. The most used systems are in vivo electroporation, protamine, cationic nanoemulsion, modified dendrimer nanoparticles, cationic liposomes, cationic polysaccharide particles, cationic polymers, and different versions of cationic lipid nanoparticles (LNPs) [26,47], many of which are now commercially available.…”