mRNA Nanoparticles Reprogramme Tumour Immune Environment

TARGETED mRNA lipid nanoparticles could help overcome the immunosuppressive environment that prevents immune cells from effectively attacking tumours, according to preclinical research.

Researchers developed antibody-coated lipid nanoparticles designed to target tumour-associated macrophages and deliver mRNA encoding the chemokine CXCL9 alongside an immune-stimulating Toll-like receptor agonist.

Targeting Tumour-Associated Macrophages

Tumour-associated macrophages can contribute to an immunosuppressive tumour microenvironment, limiting the ability of cytotoxic T lymphocytes to infiltrate and attack malignant cells.

While lipid nanoparticles carrying mRNA offer a potential way of altering this environment, conventional approaches can suffer from poor targeting, limited efficacy and unwanted toxicity.

To address this, researchers developed an antibody-coated lipid nanoparticle targeting TREM2, a receptor expressed by tumour-associated macrophages.

The particles were engineered to co-deliver CXCL9-encoding mRNA and a Toll-like receptor agonist, with the aim of simultaneously altering macrophage behaviour and attracting cytotoxic T cells into tumours.

Boosting Antitumour Immunity

The targeted delivery system reduced the immunosuppressive characteristics of the tumour microenvironment and increased both the infiltration and activity of cytotoxic T lymphocytes in preclinical models.

CXCL9 plays an important role in recruiting activated immune cells, including cytotoxic T cells, towards sites of inflammation.

By directing CXCL9 production towards tumour-associated macrophages, the researchers aimed to generate the chemokine within the tumour itself rather than exposing healthy tissues more broadly.

The approach was also tested alongside immune checkpoint inhibitors targeting PD-L1 and CTLA-4.

Combining the nanoparticle platform with checkpoint inhibition promoted an immune environment favouring cytotoxic T-cell activity and generated durable immune memory.

Potential to Improve Immunotherapy

Immune checkpoint inhibitors have transformed treatment for several cancers, but many tumours remain resistant because immune cells cannot adequately penetrate or function within the tumour microenvironment.

The findings suggest that targeted mRNA delivery could potentially complement existing immunotherapies by reprogramming this local environment.

However, the research remains preclinical. Further studies will be required to determine safety, dosing, biodistribution and efficacy in humans before the approach could progress towards clinical use.

Reference

Chen R et al. Targeting tumor-associated macrophages using mRNA lipid nanoparticles for cytotoxic T lymphocyte-mediated cancer immunotherapy. Sci Adv. 2026;12(37):eaed9568. doi:10.1126/sciadv.aed9568.

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