Nanobody Therapeutics for SARS-CoV-2 Neutralization

Nanobodies are single-domain antibody fragments derived from the heavy-chain-only antibodies of camelids or from shark IgNARs. Their small size (~12–15 kDa), high stability and ease of production in microbial systems make them attractive alternatives to conventional monoclonal antibodies. By targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein, nanobodies can directly block interaction with the human ACE2 receptor or induce conformational changes that render the spike protein inactive. Engineering into multivalent or multispecific formats enhances avidity, broadens neutralization across emerging variants and mitigates viral escape. Intranasal or aerosol delivery of thermostable nanobodies offers a non-invasive route to prophylaxis and early therapy, particularly against highly transmissible and immune-evasive strains such as Omicron. Advances in structural biology—especially cryo-electron microscopy and X-ray crystallography—have elucidated distinct neutralization mechanisms, guiding rational design of next-generation therapeutics with picomolar potency and cross-reactivity across divergent sarbecoviruses.

Research from Nature Portfolio

In 2023, novel shark-derived IgNAR nanobodies were elicited by immunising nurse sharks with SARS-CoV-2 RBD and spike nanoparticle immunogens. Two epitope-targeting families were identified: one binds a conserved lateral face of the RBD, the other overlaps the ACE2 interface. Conversion into Fc-fused chimeras conferred potent effector functions and picomolar neutralization of all major variants of concern, including Omicron BA.1 and BA.5, as well as cross-neutralization of SARS-CoV-1. Structural characterisation enabled the design of multispecific constructs with enhanced breadth and picomolar affinity across sarbecovirus clades. Earlier work isolated VHH nanobodies from camelid-engineered mice and llamas, defining two complementary groups: one recognising a highly conserved epitope rarely targeted by human antibodies, the other focusing on the ACE2-binding ridge. Homo- and heterotrimeric formats of these nanobodies overcame antigenic drift in Alpha, Beta and Gamma variants, achieving ultrapotent neutralization and demonstrating resilience to escape mutations.

Nanobody Therapeutics for SARS-CoV-2 Neutralization publication trend

The graph below shows the total number of articles in nanobody therapeutics for sars-cov-2 neutralization across all publications each year (not limited to Nature Index journals).

Technical terms

Nanobody: A single-domain antibody fragment (~12–15 kDa) derived from camelid heavy-chain antibodies or shark IgNARs, retaining full antigen-binding capacity.

VHH: The variable domain of a camelid heavy-chain antibody, equivalent to a nanobody and responsible for antigen recognition.

IgNAR: Immunoglobulin new antigen receptor, a shark-specific heavy-chain antibody format that yields single-domain binding regions.

Receptor-binding domain (RBD): The region of the SARS-CoV-2 spike protein that directly engages the ACE2 receptor to initiate viral entry.

Spike trimer: The trimeric assembly of spike glycoprotein subunits on the viral surface, mediating host-cell attachment and membrane fusion.

Multivalency: The engineering of two or more antigen-binding domains into a single molecule to increase overall binding strength (avidity) and reduce escape mutations.

References

1. A novel nanobody broadly neutralizes SARS‐CoV‐2 via induction of spike trimer dimers conformation. Exploration (2023).
2. Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity. Nature Communications (2023).
3. Therapeutic nanobodies against SARS-CoV-2 and other pathogenic human coronaviruses. Journal of Nanobiotechnology (2024).
4. A potent and broad‐spectrum neutralizing nanobody for SARS‐CoV‐2 viruses, including all major Omicron strains. MedComm (2023).
5. Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants. Nature (2021).