Engineering Interferon-γ-Enhanced Chimeric Antigen Receptor Macrophages via Lipid-Assisted Polymeric Nanoparticles for Cancer Immunotherapy.
basic_science · Level V
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- Record sourced from PubMed, PMID 42400551.
- Also identified by DOI 10.1021/acsnano.5c21015.
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Abstract
Chimeric antigen receptor macrophages (CAR-Ms) are promising in solid tumor therapy due to their tumor-penetrating property and antigen-specific phagocytosis. However, current CAR-M therapy is limited by the low <i>ex vivo</i> proliferation of macrophages and the complexity of the engineering process. Generating CAR-Ms <i>in vivo</i> can overcome these challenges but still faces an M2-like pro-tumor phenotype polarized by immunosuppressive tumor microenvironment. Herein, we devise macrophage-preferential ionizable cationic lipid-assisted polymeric nanoparticles (iCLANs) to co-deliver mRNAs encoding interferon-γ (IFN-γ) and a CAR molecule, denoted as iCLAN<sub>mCAR+mIFN-γ</sub>, enabling <i>in vivo</i> engineering of CAR-Ms with a sustained M1-like phenotype. iCLAN<sub>mCAR+mIFN-γ</sub> can coexpress IFN-γ and CAR in tumor-associated macrophages, thereby producing CAR-Ms capable of maintaining antitumor phenotype to effectively engulf tumor cells in an antigen-specific manner. Intravenous injection of iCLAN<sub>mCAR+mIFN-γ</sub> in EGFRvIII<sup>+</sup> breast tumor and CD19<sup>+</sup> B-cell lymphoma models directly generates EGFRvIII CAR-Ms or CD19 CAR-Ms within tumors, resulting in significant tumor growth inhibition and remodeling of the immunosuppressive tumor microenvironment. This study provides an efficient strategy for <i>in vivo</i> engineering of M1-like CAR-Ms for cancer therapy.