Gene therapies hold the potential to cure diseases by exploiting viruses. Genome engineering tools like CRISPR and prime editing have accelerated the prospects for this technique. However, obstacles remain in delivering therapies to target tissues safely and effectively. Capsid engineering is one avenue that shows promise in addressing these challenges.
Therapeutic uses of viruses
While many of us only think of viruses as a threat, researchers can harness them as useful medical tools—from vaccines to cancer treatments. One area that has made extensive use of viruses in this way is gene therapy. Here, researchers can use viruses as vehicles, or “vectors”, to deliver a genetic payload to a target cell. Decades of research has taught us that we can exploit viruses in this way to prevent and treat disease. In addition, we can redesign them to work even better for us.
What is a capsid?
A key part of the virus that we can re-engineer is its capsid. The capsid is a protective protein shell that surrounds the virus’ genetic material. The capsid is key to virus function, serving as a tough, yet versatile container for delivering the genetic code within. Through its specialised structure, the capsid protects the virus from immune and environmental stresses. The capsid also enables the virus to initiate infection by recognising cellular receptors.
Blueprints for a better capsid
Evolution has shaped the range of capsids found in nature. But using knowledge built up through cellular and structural biology, including techniques like electron cryo-microscopy (cryo-EM) and X-ray crystallography, we can modify them to serve as better tools for gene therapy.
What might these engineered capsids look like? Generally, capsid engineering strategies to date have had one or more of the following aims:
- Improving stability: ensuring the viral vector remains intact during storage, transport and administration.
- Reducing immunogenicity: making the capsid less visible to the patient’s immune system to avoid clearance or adverse reactions.
- Improving transduction efficiency: maximising the viral vector’s ability to enter and successfully deliver its payload to the target cell.
- Targeting new tissues: redirecting viral vectors to home in on relevant organs.
- Increasing packaging capacity: enabling the viral vector to carry a larger genetic payload.
- Expanding functionality: decorating the capsid with molecular motifs that confer additional functions, such as immune tolerisation.
Viral vectors with capsids engineered to possess these properties can be safer, as well as more effective and precise. They offer the promise of delivering large payloads to the affected part of the body with minimal immune response, remaining stable throughout handling and achieving better results with lower doses. In other words, more accessible, reliable and versatile treatments.
The capsid engineer’s toolbox
Of course, manipulating viral capsids to achieve these aims is easier said than done. However, scientists have successfully engineered capsids through several approaches (see Mol. Ther., May 2025 for examples of engineered capsids). To date, scientists have developed most engineered capsids through rational design or directed evolution.
Rational design
With rational design, scientists rely on mechanistic knowledge of the relationship between structure and function to redesign the capsid. This could be by chemically decorating the capsid with useful molecules, or swapping individual amino acids.
For example, researchers have successfully coated the adeno-associated virus (AAV) capsid with N-acetylgalactosamine. N-acetylgalactosamine is a sugar that binds to a receptor on the surface of liver cells (see Chem. Sci., Jan 2020 for capsids displaying such sugars). These modified capsids target liver cells with higher specificity, and antibodies bind to them less easily.
Scientists have also hypothesised that introducing more positively charged amino acids to the interior surface of a capsid could make it better at recruiting and compacting negatively charged DNA (see Expert Opin. Biol. Ther., Jan 2022 for suitable capsids). This could increase the packaging capacity and stability of the vector.
Directed evolution
In contrast, directed evolution approaches exploit natural evolutionary processes. Researchers are able to generate highly adapted capsids without needing to understand the underlying mechanism by iteratively introducing random differences into capsids and selecting only those with the highest stability, efficiency or specificity.
This technique was used successfully to adapt AAV for targeted delivery to muscle cells (see Cell, Sep 2021 for muscle-targeted AAVs). Researchers injected mice with a large number of modified AAV capsids, each containing different amino acids in the part of the capsid that interacts with cells. The researchers were able to identify a pattern of amino acids that targeted the capsids specifically to the muscles by analysing which of the capsids ended up in the muscle tissue. Engineered capsids with this pattern of amino acids could effectively deliver genetic payloads at doses 250 times lower than would be needed for unmodified AAVs.
The future of capsid engineering
Several gene therapy candidates with modified capsids are already in clinical trials and, as researchers expand capsid engineering strategies, this trend looks set to continue.
New technologies are also set to disrupt the field. In particular, machine learning can be used to rapidly analyse vast datasets and identify unseen patterns in the relationship between capsid structure and function. This could help researchers to design adapted capsids in a fraction of the time required by traditional methods.
Protecting your engineered capsids – how we can help
Indeed, any of the developments described above could potentially form the basis of a patent application. Such a patent application could be useful to provide a competitive edge, as it could provide an obstacle to competitors using a similar capsid having the same improved properties.
Capsids possess complex structures, and so careful thought should be given to how to claim these appropriately. For example, in AAV, different splice variants of the same gene encode the VP1, VP2 and VP3 proteins, and careful thought needs to be given when considering how to claim sequences of such splice variants.
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