In Vitro-Transcribed mRNAs as a New Generation of Therapeutics in the Dawn of Twenty-First Century: Exploitation of Peptides as Carriers for Their Intracellular Delivery

Abstract

In vitro-transcribed mRNAs (IVT-mRNAs) are easily and rapidly designed in vitro synthesized RNA molecules. After their intracellular delivery through an efficient delivery system, the host cell ribosomes will be recruited to translate and produce the corresponding desired proteins. Nowadays, about 20 years after the first report as for the use of IVT-mRNA, this technology has all the spotlight on it, due to the recently produced vaccines against SARS-CoV-2. All this enthusiasm around IVT-mRNA has pushed a wave of biotech companies to leverage this technology, raising significant investments annually. Thus, IVT-mRNA technology has gained an impressive dynamic, with multidimensional applications [as protein replacement therapy (PRT), cancer immunotherapy, vaccine production, production of antibodies, cytokines and growth factors, gene silencing, cellular reprogramming, and gene editing] with remarkable results. This chapter will emphasize the recent advances in IVT-mRNA delivery. A wide range of in vitro and in vivo transfection reagents have been shown to protect IVT-mRNA from degradation, to escape immunosurveillance and facilitate its intracellular delivery. IVT-mRNA delivery systems can be classified into two broad categories: (i) physical transfection methods, like electroporation, that temporarily disrupt cell membrane barrier function and (ii) chemically formulated nanocarriers, like polymer-based, lipid-based nanovectors, lipid–polymer hybrid nanoparticles, and peptide vectors. As the peptide-based delivery systems are gaining ground due to the flexibility that peptides can offer, this chapter will present this very interesting aspect that combines IVT-mRNA technology with protein transduction domain (PTD) technology. Compared to cationic polymers, the peptides are of low-molecular weight, with degradable amino acid sequences and distinct biological properties, such as cell permeability efficiency and cell and nuclear surface targeting. Either by non-covalent or covalent binding, peptide-based carriers and hybrids are suggested as interesting alternatives to the various existing non-viral vectors for IVT-mRNA delivery. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.