In vivo CAR engineering for immunotherapy

Yan-Ruide Li^#^{1

2}, Yichen Zhu^#^{1

2}, Tyler Halladay^{1

2}, Lili Yang^{3

4

5

6

7

8}

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁴ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁶ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁷ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁸ Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.

^# Contributed equally.

PMID: 40379910
DOI: 10.1038/s41577-025-01174-1

Review

In vivo CAR engineering for immunotherapy

Yan-Ruide Li et al. Nat Rev Immunol. 2025 Oct.

. 2025 Oct;25(10):725-744.

doi: 10.1038/s41577-025-01174-1. Epub 2025 May 16.

Authors

Yan-Ruide Li^#^{1

2}, Yichen Zhu^#^{1

2}, Tyler Halladay^{1

2}, Lili Yang^{3

4

5

6

7

8}

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁴ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁶ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁷ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.
⁸ Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA, USA. liliyang@ucla.edu.

^# Contributed equally.

PMID: 40379910
DOI: 10.1038/s41577-025-01174-1

Abstract

Chimeric antigen receptor (CAR)-engineered immune cell therapy represents an important advance in cancer treatments. However, the complex ex vivo cell manufacturing process and stringent patient selection criteria curtail its widespread use. In vivo CAR engineering is emerging as a promising off-the-shelf therapy, providing advantages such as streamlined production, elimination of patient-specific manufacturing, reduced costs and simplified logistics. A large set of preclinical findings has inspired further investigation into treatments for hard-to-treat diseases such as solid tumours and has facilitated the development of advanced products to enhance in vivo CAR engineering efficacy, the persistence of the cellular therapeutic and safety. In this Review, we summarize current in vivo CAR engineering strategies, including nanoparticle-based and viral delivery systems as well as bioinstructive implantable scaffolds, and discuss their advantages and disadvantages. Additionally, we provide a systematic comparison between in vivo and conventional ex vivo CAR engineering methods and address the challenges and future prospects of in vivo CAR engineering.

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Conflict of interest statement

Competing interests: L.Y. is a scientific adviser to AlzChem and Amberstone Biosciences, and a cofounder, stockholder and advisory board member of Appia Bio. None of the declared companies contributed to this study. The other authors declare no competing interests.

References

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In vivo CAR engineering for immunotherapy

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In vivo CAR engineering for immunotherapy

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Abstract

Conflict of interest statement

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Medical