Colorectal cancer: mRNA nanobodies open a new avenue in immunotherapy

By Elodie Vaz | Published on March 11, 2026 | 3 min read

Colorectal cancer remains a major challenge in oncology. Immunotherapies targeting immune checkpoints have transformed the management of many tumors, but their effectiveness in this disease remains limited.

Most patients present with so-called microsatellite-stable tumors, which are poorly responsive to treatments targeting the PD-1/PD-L1 immune checkpoint axis. The monoclonal antibodies currently used also have several limitations. Their large size reduces their penetration into tumors, they can cause immune-related adverse effects, and their production remains costly. In some aggressive forms linked to chronic intestinal inflammation—such as colitis-associated colorectal cancer—these treatments are often largely ineffective.

Testing a new generation of miniature antibodies

In a study published in eGastroenterology, researchers explored an innovative approach based on mRNA-encoded nanobodies. Nanobodies are tiny single-domain antibodies originally discovered in camelids and sharks. Their size—around 15 kDa compared with 150 kDa for a conventional antibody—allows them to penetrate tumor tissues more efficiently while maintaining strong binding affinity.

However, this small size also presents a drawback. Nanobodies are rapidly cleared by the kidneys. To overcome this limitation, the researchers designed a “quadruple” nanobody, combining four anti-PD-L1 nanobodies linked together by flexible connectors. The goal was to increase the molecule’s circulation time while preserving its advantages.

An administration strategy inspired by mRNA vaccines

To produce these nanobodies in the body, the team used a delivery technology based on lipid nanoparticles containing modified mRNA. This strategy, popularized by COVID-19 vaccines, enables cells to directly produce the therapeutic molecule.

The researchers designed two versions: a monomeric form and a quadruple form. These constructs were tested in several mouse models of colorectal cancer to evaluate their antitumor efficacy.

Markedly superior results with the quadruple nanobody

The results show a clear difference between the two formats. While mRNA encoding a single nanobody slightly slowed tumor growth, the quadruple version showed much greater efficacy. It remained in the bloodstream about twice as long and maintained higher therapeutic concentrations.

In mice bearing sporadic colorectal tumors, four injections of lipid nanoparticles significantly slowed tumor progression, with visible effects after the third administration.

The approach proved even more notable in models of colitis-associated colorectal cancer, a situation in which conventional anti-PD-L1 antibodies generally fail. The treatment reduced both the incidence and number of tumors.

Analyses also showed remodeling of the tumor microenvironment: a decrease in immunosuppressive myeloid-derived cells and tumor-associated macrophages, alongside an increase in CD8+ T lymphocytes, which are essential for anticancer immune responses.

Toward new therapeutic strategies

Researchers also observed that mRNA nanoparticles could directly influence immune cell development. In vitro, they inhibit the differentiation of hematopoietic stem cells into macrophages and reduce the expression of several immunosuppressive markers.

This preclinical study therefore suggests that mRNA-encoded anti-PD-L1 nanobodies could represent a new immunotherapy approach for patients with colorectal cancer. In the future, researchers are considering combination strategies involving multiple nanobodies targeting different immune checkpoints or combining them with chemotherapy or radiotherapy. Such approaches could open the way to more effective treatments for colorectal cancers that are currently resistant to immunotherapy.




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About the Author – Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on human life. A registered nurse since 2010, she spent twelve years at patients’ bedsides before exchanging her stethoscope for a notebook. She now investigates the links between environment and health, convinced that the vitality of life cannot be reduced to that of human.