Science advancesSep 11, 2026

Using mRNA lipid particles to direct immune cells that kill cancer by targeting tumor-supporting macrophages

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 12, 2026

Abstract

An antibody-coated lipid nanoparticle delivery system effectively targets tumor-associated macrophages to enhance cytotoxic T lymphocyte activity.

The immunosuppressive tumor microenvironment limits the effectiveness of immunotherapy.
Lipid nanoparticles carrying messenger RNA may offer a way to modify this environment.
Codelivery of a Toll-like receptor agonist and CXCL9-encoding mRNA in the antibody-coated lipid nanoparticles improved tumor infiltration and CTL activity.
Combining this delivery system with immune checkpoint inhibitors against PD-L1 and CTLA-4 may create a more favorable environment for CTLs.
This approach could potentially improve responses to cancer immunotherapy by reprogramming the immunosuppressive tumor microenvironment.

Simplified

The immunosuppressive tumor microenvironment (TME) remains one of the main obstacles that limit responsiveness to immunotherapy. Recently, lipid nanoparticles carrying messenger RNA (mRNA) have emerged as a promising strategy to modulate the immunosuppressive TME, with the ultimate goal of sustaining anticancer immunity of cytotoxic T lymphocytes (CTLs). However, there are challenges with mRNA-based cytokine/chemokine therapies such as the lack of specific targeting, low therapeutic efficacy, and elevated toxicity, raising concerns about their clinical translation. Here, we have developed an antibody-coated lipid nanoparticle (Ab-LNP) delivery system that targets the protein triggering receptor expressed on myeloid cells 2 (TREM2) expressed by tumor-associated macrophages (TAMs). We demonstrate that codelivery of a Toll-like receptor agonist and CXCL9-encoding mRNA encapsulated in our Ab-LNP successfully ameliorates immunosuppression and improves tumor infiltration and activity of CTLs. Further combination with immune checkpoint inhibitors against PD-L1 and CTLA-4 promoted a CTL-favoring immunological environment and durable memory immunity. Our Ab-LNPs targeting TAMs highlight the potential of reprogramming immunosuppressive TME to enhance CTL activity for improved response to cancer immunotherapy.

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Using mRNA lipid particles to direct immune cells that kill cancer by targeting tumor-supporting macrophages

Abstract

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