Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking

Abstract

The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system (CNS), and muscles. However, achieving effective delivery of oligonucleotide therapeutics to specific tissues still remains a major challenge, limiting their widespread use. Chemical modifications play a crucial role to overcome biological barriers to enable efficient oligonucleotide delivery to the tissues/cells of interest. They provide oligonucleotide metabolic stability and confer favourable pharmacokinetic/pharmacodynamic properties. This review focuses on the various chemical approaches implicated in mitigating the delivery problem of oligonucleotides and their limitations. It highlights the importance of linkers in designing oligonucleotide conjugates and discusses their potential role in escaping the endosomal barrier, a bottleneck in the development of oligonucleotide therapeutics.

Impact of the Core Chemistry of Self‐Assembled Spherical Nucleic Acids on their In Vitro Fate

“…The rate of this cleavage after incubation with DNAse I was analyzed by PAGE (Figure 7B, S15–S17) and showed that C 6 is cleaved at a lower rate than all S 6 SNAs, crosslinked or not. After the action of endonucleases in the endolysosomal network, [39,40] several pathways of endosomal escape could occur for the FASO, as described in the literature [41,42] . The intracellular trafficking of phosphorothioated oligonucleotides has been widely studied and explains their higher activity as compared to non‐modified ASOs [43–45] .…”

“…After the action of endonucleases in the endolysosomal network, [39,40] several pathways of endosomal escape could occur for the FASO, as described in the literature. [41,42] The intracellular trafficking of phosphorothioated oligonucleotides has been widely studied and explains their higher activity as compared to non-modified ASOs. [43][44][45] From these experiments, S 6 and S 6x SNAs show the most promise for unaided gene silencing, as they are able to dissociate intracellularly due to their bioreducible core and release the FASO therapeutic the most efficiently.…”