VHH-enabled AOCs for targeted therapeutic delivery

Receptor-mediated intracellular delivery of gene-modulating oligonucleotides beyond liver-focused systems

Scientific & Therapeutic Context

What are AOCs?

Antibody-oligonucleotide conjugates (AOCs) are targeted biotherapeutics that combine a targeting ligand- such as full antibodies, fragments, or single-domain VHH antibodies- with a gene-modulating oligonucleotide payload like siRNA or antisense oligonucleotides. A linker chemistry connects the two, enabling controlled delivery and release. AOCs are designed to deliver nucleic acids precisely to specific cell types through receptor-mediated uptake, overcoming challenges of traditional RNA delivery.

Delivery landscape for RNA therapeutics

Current Delivery Approaches

Existing delivery technologies such as GalNAc conjugates and lipid nanoparticles have enabled significant clinical progress in RNA therapeutics. However, these systems predominantly accumulate in hepatic tissues, restricting their use for diseases requiring extrahepatic or cell-specific targeting.

Where AOCs Fit

AOCs represent an emerging delivery strategy designed to extend nucleic acid therapies beyond the liver. By leveraging antibody-based targeting and conjugation approaches adapted from antibody-drug conjugates, AOCs enable receptor-defined delivery to specific cell populations, supporting more precise and modular therapeutic design.

Why VHH antibodies for AOC design?

To fully realise receptor-defined delivery, the choice of targeting ligand is critical. VHH single-domain antibodies provide a compact, highly engineerable format capable of accessing difficult epitopes while supporting flexible conjugation strategies making them well suited for next-generation AOC strategies. For example, when integrated with AOC strategies, VHH can facilitate delivery of therapeutic payloads across the blood-brain barrier, enabling precise targeting of disease-associated antigens in the central-nervous system (CNS).