Nucleic acid therapeutics hold immense promise and getting them where they need to go remains one of biotechnology’s greatest challenges. Their size and negative charge can limit cellular uptake, while biological barriers influence which tissues they can reach after administration. As a result, delivery has become an important part of oligonucleotide drug design.
Successful delivery means that the oligonucleotide therapeutic enters the body and then reaches the intended tissue, and there, enters relevant cells where it can exert its molecular effect. Unsurprisingly, engineering an effective delivery pathway is heavily dependent on the molecular target and tissue.
One of the most established approaches for liver-targeted oligonucleotides is GalNAc conjugation. GalNAc is attached directly to the oligonucleotide and facilitates uptake into hepatocytes. This strategy is used by several approved siRNA therapeutics and has also been applied to antisense oligonucleotides.
Lipid nanoparticles, or LNPs, provide another delivery option. They encapsulate RNA molecules and can protect their cargo while supporting cellular uptake. LNPs became widely known through their use in mRNA vaccines and are also used for some approved siRNA-based medicines.
Not every oligonucleotide requires a separate carrier. Some therapeutics - most of the currently approved ASO medicines - can be administered directly to reach the relevant biological compartment. Intrathecal administration, for example, can provide oligonucleotides with access to the central nervous system. Due to their comparatively high concentration they are being uptaken by cells by active and passive ways of transportation that are not yet fully understood.
Delivering oligonucleotides efficiently to tissues beyond the liver remains an important area of research. New ligand-based approaches and engineered delivery systems are being investigated to improve uptake by particular cell types and expand the range of tissues that can be addressed. Conjugation with Peptides (Peptide-oligonucleotide conjugates, or POC) and antibodies (antibody-oligonucleotide conjugates, AOC) are on the frontier of new approaches for targeted and effective delivery.
Many of these technologies are still at earlier stages of development. Their potential therefore needs to be considered alongside questions of efficacy, safety, manufacturability and clinical translation.
Delivery helps determine which biological targets can realistically be addressed with oligonucleotide therapeutics. Improvements in tissue targeting and cellular uptake could therefore expand the range of diseases accessible to these medicines and create new possibilities beyond the tissues that can already be reached effectively today.
A complete list of currently approved oligonucleotide therapeutics is available here:
Browse approved oligo therapeutics
For a compact summary of the landscape download our overview: