Peptide-based nanoparticles for extrahepatic delivery of therapeutic RNA
RNA therapeutics has evolved tremendously during the las two decades. Eighteen RNA medicines are now on the market, but major challenges still remain. These challenges include finding strategies to enable the use of RNA therapeutics outside the liver in a safe and efficacious manner. This overview summarises the advances that industrial peptide-based nanoparticles are making on their way to the clinic. Peptide-based platforms offer significant advantages to deliver RNA medicines extrahepatically, including liver avoidance, decreased immunotoxicity and enhanced endosomal release.
The field of RNA therapeutics has significantly evolved since the first FDA approval of an RNA-based drug in 1998. Fomivirsen, now withdrawn, is an antisense oligonucleotide administered through intravitreal injections for treating cytomegalovirus retinitis in patients with a compromised immune system. With eighteen RNA medicines approved by the FDA and/or EMA, including one aptamer, nine antisense oligonucleotides, five short interfering RNAs (siRNAs), and two messenger RNAs (mRNAs) (Table 1), RNAs are on their way to becoming mainstream drugs. However, the application of RNA therapeutics is still restricted to a few disease areas: liver regulation of gene expression, a limited number of rare genetic diseases, and vaccines.
Except for some aptamers, RNA modalities require entering the cell to exert their action. Natural RNA is unstable, hydrophilic, polyanionic, too large to cross biological membranes, and able to elicit an immune response leading to the destruction of the administered RNA or activation of inflammatory cascades (1). Decades of research have led to the discovery of strategies to overcome some of the in ...