Naked RNA drugs will degrade rapidly as there are a large number of RNases in the blood, it will affect the drug efficacy of RNAi. Therefore, it's very important to improve the stability of naked RNA. Except for chemically modification, researchers are working hard on siRNA drug delivery system nowadays. Drug delivery system is becoming an important tool for delivering the candidate siRNA drugs to target cells.
In August 2018, the US FDA approved the first siRNA drug, called ONPATTRO™ (Patisiran) by Alnylam Pharmaceuticals, for the treatment of hereditary transthyretin polyneuropathy. This was an important milestone for the field of siRNA drugs and opens the door for the research of other siRNA drug delivery system.
Here are the delivery systems and their mechanisms and some typical examples.
|Delivery systems||Mechanisms||Typical Examples|
|Lipophilic siRNA derivates||EPR, increased circulation half-life, receptor-mediated endocytosis, pH-induced lipid ionization and membrane disruption, peptide-induced membrane fusion||Cholesterol-siRNA, lipid-based nanoparticles (LPNs)|
|siRNA-receptor ligand||Receptor-mediated endocytosis, systemic circulation via subcutaneous injection||GalNAc-siRNA|
|siRNA-antibody||Receptor-mediated endocytosis, long circulation half-life mediated by Fc domain, release of payload by catabolism of antibody||THIOMAB-siRNA|
|siRNA-aptamer||Receptor-mediated endocytosis||CCR5 aptamer– DsiRNA, gp120 aptamer–DsiRNA|
|siRNA-cpG oligonucleotide||TLR9 binding to CpG (immune-stimulatory), nonspecific uptake via gymnosis||CpG(A)–STAT3 siRNA|
|siRNA-peptide||Targeted or non-targeted uptake, enhanced endosomal escape||Penetratin–siRNA|
|Dynamic polyconjugate of siRNA||Targeted or non-targeted uptake, enhanced endosomal escape||polyarginine– siRNA|
|Exosomes||Increased circulation half-life via CD47 expression, receptor-mediated uptake||Exosome delivery of KRAS siRNA, exosome delivery to CNS|
Figure 1. A scheme of siRNA bioconjugates