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Engineering Interferon-γ-Enhanced Chimeric Antigen Receptor Macrophages via Lipid-Assisted Polymeric Nanoparticles
Yi-Qun Sun1, Hong-Min Shang1, Mei-Dan Wang1
1School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China.
ACS Nano
|July 4, 2026
Summary
This study introduces a novel nanoparticle system for in vivo engineering of chimeric antigen receptor macrophages (CAR-Ms). This approach overcomes challenges in CAR-M therapy, promoting an anti-tumor phenotype for enhanced cancer treatment.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Chimeric antigen receptor macrophages (CAR-Ms) show promise for solid tumor therapy due to tumor penetration and antigen-specific phagocytosis.
- Current CAR-M therapy faces limitations including low ex vivo macrophage proliferation and complex engineering processes.
- In vivo generation of CAR-Ms is challenging due to the immunosuppressive tumor microenvironment promoting a pro-tumor M2-like phenotype.
Purpose of the Study:
- To develop an efficient in vivo strategy for engineering CAR-Ms with a sustained M1-like anti-tumor phenotype.
- To overcome the limitations of ex vivo CAR-M generation and the pro-tumor polarization in the tumor microenvironment.
Main Methods:
- Development of macrophage-preferential ionizable cationic lipid-assisted polymeric nanoparticles (iCLANs) for co-delivery of mRNA encoding interferon-γ (IFN-γ) and a CAR molecule.
- In vivo administration of iCLANs (iCLANmCAR+mIFN-γ) to tumor-associated macrophages.
- Evaluation of CAR-M generation, phenotype, and therapeutic efficacy in EGFRvIII+ breast tumor and CD19+ B-cell lymphoma models.
Main Results:
- iCLANmCAR+mIFN-γ successfully co-delivered mRNA, leading to in vivo expression of IFN-γ and CAR in tumor-associated macrophages.
- Generated CAR-Ms maintained a sustained M1-like anti-tumor phenotype, enhancing antigen-specific phagocytosis.
- Significant tumor growth inhibition and remodeling of the immunosuppressive tumor microenvironment were observed in preclinical models.
Conclusions:
- This study presents an efficient strategy for in vivo engineering of M1-like CAR-Ms using iCLAN nanoparticles.
- The developed approach holds potential for advancing CAR-M based cancer immunotherapy by enabling direct in vivo CAR-M generation.
- This method offers a promising alternative to complex ex vivo engineering, addressing key challenges in current CAR-M therapy.
