The oligonucleotide therapeutics market is expanding at pace, with more than 20 synthetic oligonucleotides already approved and around 700 in development.
As the pipeline grows, so too does pressure on contract development and manufacturing organisations (CDMOs) to solve one of the field's most persistent challenges: getting these therapies to the right tissue, in sufficient quantities, with acceptable tolerability.
According to Daniel Pfeffer, Director of Oligonucleotide Production at Bachem, conjugation chemistry is emerging as one of the most powerful tools available to meet that challenge.
He says that oligonucleotides (including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) and RNA aptamers) offer highly targeted mechanisms of action, modulating gene expression with a precision that makes them particularly promising for conditions that have historically been difficult to treat, from cardiovascular disorders to central nervous system diseases.
Yet, despite their therapeutic promise, they do face well-documented delivery limitations: susceptibility to nuclease degradation, rapid renal and hepatic clearance, poor cellular uptake and insufficient tissue selectivity.
Conjugation chemistry addresses these barriers directly by linking oligonucleotides to peptides, antibodies, carbohydrates, or other functional moieties.
The result is a more stable, tissue-selective molecule that reaches its intended target more efficiently and, in some cases, enables lower or less frequent dosing, with corresponding benefits for patient tolerability and convenience.
Using peptides to improve oligonucleotide delivery
Peptide-oligonucleotide conjugates (POCs) represent one of the most clinically relevant approaches.
Cell-penetrating peptides (CPPs) facilitate cellular entry and endosomal escape, while receptor-targeting peptides direct therapies to tissues where specific receptors are overexpressed.
Examples already demonstrate the clinical value of this approach: cRGD-siRNA conjugates targeting αvβ3 integrin receptors have shown significant tumour volume reduction in preclinical models and GLP1R-ASO conjugates have demonstrated improved gene silencing in pancreatic β-cells, illustrating how precise delivery benefits patients clinically.
Selecting the right conjugation strategy, however, is critical. CDMOs have a range of chemistries at their disposal, including thiol-maleimide reactions, disulfide linkages, click chemistry via copper-catalysed or copper-free azide-alkyne cycloadditions and amide bond formation.
Each has distinct advantages depending on the oligonucleotide, the target tissue and the required in vivo stability profile.
No single approach suits every programme and the choice of chemistry can meaningfully influence both therapeutic efficacy and manufacturability.
Manufacturing considerations
Manufacturing peptide-oligonucleotide conjugates demands specialist expertise across both peptide and oligonucleotide chemistry.
Solid-phase synthesis is well-suited to shorter constructs, enabling conjugates to be assembled in a single sequence with fewer purification steps, whereas post-synthetic conjugation is used for longer peptides or full proteins.
Both approaches are scalable to GMP production, supporting the translation of early research into clinically viable therapies.
Advancing therapies with TIDE innovation
Pfeffer argues that CDMO innovation in this space, which Bachem terms TIDE (Targeted Innovative Delivery), is now central to the continued growth of the oligonucleotide sector.
By optimising conjugation parameters, CDMOs can help customers improve cellular uptake, tissue specificity and molecular stability, ultimately helping bring next-generation oligonucleotide treatments to patients more efficiently and at greater scale.