Lung metastasis and recurrence is mitigated by CAR macrophages, in-situ-generated from mRNA delivered by small extracellular vesicles

Yuchen Xiao, Tianchuan Zhu, Zhenxing Chen and Xi Huang ()
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Yuchen Xiao: The Fifth Affiliated Hospital of Sun Yat-sen University
Tianchuan Zhu: The Fifth Affiliated Hospital of Sun Yat-sen University
Zhenxing Chen: Kingcell Regenerative Medicine (Guangdong) Co.
Xi Huang: The Fifth Affiliated Hospital of Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract Cancer metastasis and recurrence remain the leading causes of cancer-related mortality, and lung is a major metastatic anatomical location. Chimeric antigen receptor macrophages (CAR-M) represent promising candidates for cancer therapy owing to their superior tumour-infiltrating and antigen-specific phagocytotic abilities, and to being professional antigen presenting cells. However, broader applications of CAR-Ms face challenges such as complex manufacturing processes and predominant accumulation in the liver following intravenous administration. Here we present an inhalable engineered small extracellular vesicle (sEV), which contains mesothelin-specific CAR messenger RNA (CARmRNA@aCD206 sEVs) for in situ generation of CAR-Ms. The sEVs are surface-integrated with anti-CD206 single-chain variable fragments (scFv) to target CD206-expressing, immunosuppressive (M2 phenotype) macrophages. The results in mouse models suggest that inhaled CARmRNA@aCD206 sEVs could accumulate in lung tissue and deliver CAR mRNA specifically to macrophages, facilitating in situ CAR-M production. In a lung metastasis model, inhaled CARmRNA@aCD206 sEVs effectively inhibit tumor growth and prime long-term memory immunity to prevent tumour recurrence. Collectively, our engineered sEV delivery platform demonstrates capability to selectively deliver CAR mRNA to macrophages in lung tissue, providing a promising immunotherapy strategy to effectively combat lung metastasis and recurrence via generation of CAR-Ms in situ.

Date: 2025
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DOI: 10.1038/s41467-025-62506-2

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