VHH-enabled AOCs for targeted therapeutic delivery

Receptor-mediated intracellular delivery of gene-modulating oligonucleotides beyond liver-focused systems
What are VHH antibodies?

Scientific & Therapeutic Context​

What are AOCs?

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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).

Diagram of antibody/antibody fragments + oligonucleotide 

From target to functional AOC candidate

AOCs based on VHH antibodies follow a structured discovery and optimisation workflow:

 

Expanding RNA therapeutics beyond the liver

VHH-enabled AOCs are being explored across multiple therapeutic areas where cell-specific delivery remains a barrier.

Neuromuscular disorders

CNS disorders

Oncology RNA therapy

Immune cell targeting

Rare genetic diseases

Why partner with Isogenica?

  At Isogenica we can combine VHH discovery with conjugation and scalable manufacturing capabilities to support targeted therapeutic development. Site-specific engineering, such as C-terminal cysteine incorporation, has enabled controlled bioconjugation of our VHH across multiple delivery formats (LNPs and ADCs). Supported by large synthetic libraries and discovery technologies such as phage and CIS display, the platform enables efficient identification and development of VHH candidates suitable for downstream therapeutic applications.   
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VHH and the blood–brain barrier challenge

VHH and the blood–brain barrier challenge

The blood–brain barrier remains a critical bottleneck in CNS drug delivery, excluding nearly all biologics. VHH antibodies offer a practical route forward, combining small size, stability, and engineering flexibility to enable receptor-mediated transport into the brain. This article examines transport mechanisms, emerging applications, and how synthetic VHH libraries support the development of brain-penetrant biologics. Read more

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Curious how VHHs could accelerate your therapeutic program? Talk to our scientists. 

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Explore the science behind our antibody discovery platforms

Access our latest white papers and application notes to see how Isogenica’s synthetic VHH technologies are accelerating innovation in CAR-T, bispecifics, and immuno-oncology.
White Paper “Data-Driven Validation of Synthetic VHHs”
This white paper provides a data-driven validation of Isogenica’s synthetic VHH libraries, powered by Colibra® technology. Designed for biotech and pharmaceutical scientists, it demonstrates how these libraries enhance and accelerate drug discovery, particularly in oncology and immunotherapy.   Download
Extending half-lives of VHH antibodies
Because VHHs are small, they can be cleared quickly from the bloodstream. This can be a useful feature for some applications, but often a longer plasma half-life is desirable. DOWNLOAD
Advantages of VHH in bi-specifics
To learn more about the application of VHHs in bi-specifics, we have condensed our expertise into a downloadable Application Note. DOWNLOAD
Optimizing CAR-T and T-cell antibody engagers: a role for VHH single domain antibodies
This whitepaper summarises the clinical and research landscape for CAR-T and T-cell engaging antibody therapies and show how single domain VHH antibodies can be applied to optimise the next generation of these important new therapeutic modalities. DOWNLOAD
Isogenica’s PD-L1 VHH as Functional Antagonists
PD-1 is an immune checkpoint protein expressed on the surface of multiple types of immune cells, including antigen-stimulated T-cells and tumour specific T-cells1. Interaction between PD-1 and its ligands (PD-L1 or PD-L2), is responsible for the regulation of T-cell activation, apoptosis, proliferation and cytokine production. DOWNLOAD
Anti-LRP5/6 VHH inhibits WNT pathway and prevents tumour growth
VHH are the variable domain of heavy chain only antibodies. They are small in size (~15 kD) and biophysically robust. With tunable half-lives, these antibodies are ideal for targeting inaccessible epitopes, achieving enhanced tissue penetration, multi-target binding and formatting for payload delivery… DOWNLOAD
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