Lipid nanoparticles deliver mRNA to reprogram tumour macrophages and boost T-cell attack in mice

# What this study did Researchers at the University of Adelaide developed lipid nanoparticles that home to tumour-associated macrophages (TAMs) and deliver a two-part payload: an mRNA encoding the chemoattractant CXCL9 and the small-molecule immune modulator Resiquimod. The particles were coated with an antibody that recognises TREM2, a protein found at high levels on TAMs. The aim was to reprogram macrophages inside the tumour so they stop suppressing immunity and instead recruit and support cytotoxic CD8+ T cells.

# How the approach works, step by step

• Targeting: Nanoparticles are coated with an antibody against TREM2 to preferentially enter TAMs within tumours.
• Payload 1 (mRNA): Encodes CXCL9, a chemical signal that draws CD8+ T cells into the tumour microenvironment.

• Expected cascade: Reprogrammed macrophages produce CXCL9, attract CD8+ T cells, and reduce local immunosuppression so T cells remain active against cancer cells.

# Key experimental results (mouse models)

• Suppressive macrophages fell by more than 60% after treatment.
• Intratumour CXCL9 levels increased about fourfold.
• Researchers observed higher numbers and increased activity of cancer-fighting CD8+ T cells in treated tumours.
• The treatment produced a moderate reduction in tumour growth in the mouse model used.

# Combining with immune checkpoint blockade The team tested the nanoparticle treatment together with existing checkpoint inhibitors that target PD-L1 and CTLA-4. The combination led to larger increases in effector T cells and the emergence of central memory T cells, which are important for longer-term immune recall. However, in this specific mouse model the combination did not produce additional reduction in tumour size beyond what the nanoparticle treatment alone achieved.

# Why this matters

# Practical next steps and limits reported by the authors

• Questions remain about efficacy across tumour types, durability of response, optimal dosing, safety, and whether the approach will produce measurable tumour shrinkage in human cancers.
• The combination with checkpoint inhibitors changed the immune cell profile but did not improve tumour-size outcomes in the tested model, indicating that immune changes do not always translate directly to faster tumour regression.

# Bottom line Targeted lipid nanoparticles that deliver CXCL9 mRNA plus Resiquimod to TREM2-expressing TAMs altered the tumour microenvironment in mice, reduced suppressive macrophages, and increased recruitment and activity of CD8+ T cells. Results provide a preclinical foundation for exploring macrophage-directed mRNA therapies as a way to enhance immunotherapy for solid tumours, while highlighting remaining translational questions.