mRNA therapy restores immune function in ageing mice by turning the liver into a temporary immune organ

A recent study has reported that a short-acting mRNA therapy can rejuvenate immune function in older mice by compensating for age-related thymus decline, restoring vaccine responses and improving tumour control

Researchers from the German Cancer Research Center, the Heidelberg Institute for Stem Cell Technology and Experimental Medicine and the Broad Institute, in Heidelberg, Germany, have shown that age-weakened immune systems can regain function through a novel strategy employing messenger RNA (mRNA). The team demonstrated that mRNA can temporarily reprogramme the liver of older mice to produce immune regulatory signals that are normally lost with age. This intervention restored the production of immune cells, strengthened responses to vaccination and enabled older animals to mount effective anti-tumour immunity.

Ageing is accompanied by a steady decline in immune competence. Susceptibility to infection increases, vaccines lose effectiveness and the risk of cancer rises as immune surveillance weakens. A central driver of this process is the age-related shrinking – or involution – of the thymus, a small organ above the heart that supports the maturation of T lymphocytes during childhood and early adulthood. As the thymus ages, its output of naive T cells falls, and the diversity of antigens it produces in recognition of pathogenic threats narrows leading  to decline the immune responsiveness overall.

“Much has already been [tried] to halt or reverse the age-related involution of the thymus… without much success so far,” said Dr. Mirco Friedrich of the German Cancer Research Center, the Heidelberg Institute for Stem Cell Technology and Experimental Medicine and the Broad Institute.

In collaboration with colleagues in Feng Zhang’s laboratory at the Broad Institute in Cambridge, Massachusetts, United States, Friedrich pursued an alternative strategy that did not seek to repair the thymus itself.

The researchers first sought to identify which molecular signals decline most markedly with age. Through detailed single-cell analyses of immune tissues, they found that three signalling pathways showed pronounced reduction:

• notch signalling
• FMS-like tyrosine kinase 3 ligand
• interleukin-7.

Each plays a critical role in T-cell development within the thymus and supports the function of key immune cell populations.

Rather than attempting to restore thymic structure, the team asked whether these missing signals could be supplied elsewhere. They designed a combination of three mRNA molecules encoding the relevant signalling factors and packaged them into lipid nanoparticles. After administration in mice, the nanoparticles entered liver cells, which then transiently produced the required immune-regulatory proteins and released them into the bloodstream.

The effects were substantial with older mice showing a renewed production of naive T cells and demonstrating a markedly improved ability to respond to unfamiliar pathogens. Alongside this effect, the function of dendritic cells and B cells – which also decline with age – were seen to improve.

These cellular changes translated into stronger responses to vaccination. In the study, vaccine efficacy in older animals approached levels that are seen in younger mice, corresponding to a rejuvenation of immune responsiveness by several months, a meaningful shift given the relatively short lifespan of mice.

Following treatment, increased numbers of cytotoxic CD8 T cells infiltrated tumour tissue and the animals responded more effectively to cancer immunotherapies, including immune checkpoint inhibitors, which are typically less effective in older individuals as anti-tumour immunity improved. In aggressive melanoma models, tumour growth was completely suppressed in some treated mice, an outcome not observed in untreated age-matched controls.

In designing the therapy, the researchers made it act only for a limited period with mRNA expression in the liver persisting only briefly, after which protein production declined and ceased. This transient activity allowed careful dose control and reduced the likelihood of long-term adverse effects. The study reported no evidence of autoimmune reactions or liver toxicity.

By using the liver as a temporary immune signalling hub, the approach bypassed the need to regenerate the thymus itself. The liver is well suited to this role, as it naturally secretes large quantities of proteins into circulation and retains substantial synthetic capacity even in advanced age. The authors suggested that the same strategy could, in principle, allow replacement of other age-sensitive factors that contribute to immune decline.

“The immune system ages but it does not irreversibly lose its capabilities. If we [can] provide it with the missing signals again, it can… perform amazing feats,” said Friedrich.

Beyond vaccines, the findings highlight the broader potential of modern mRNA technologies as precise, time-limited tools to restore biological functions that deteriorate with age.

For further reading please visit: 10.1000/s41586-025-09873-4