In vivo human T cell engineering with enveloped delivery vehicles

Hamilton, Jennifer R.; Chen, Evelyn; Perez, Barbara S.; Sandoval Espinoza, Cindy R.; Kang, Min Hyung; Trinidad, Marena; Ngo, Wayne; Doudna, Jennifer A.

doi:10.1038/s41587-023-02085-z

Title: In vivo human T cell engineering with enveloped delivery vehicles

Journal Article · 11 January 2024 · Nature Biotechnology

DOI: https://doi.org/10.1038/s41587-023-02085-z · OSTI ID:2337619

^[1];

^[1]; Perez, Barbara S. ^[2];

^[2]; Kang, Min Hyung ^[2]; Trinidad, Marena ^[2]; Ngo, Wayne ^[3];

^[4]

Univ. of California, Berkeley, CA (United States); Azalea Therapeutics, Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States)
Gladstone Institutes, San Francisco, CA (United States); Univ. of California, Berkeley, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States); Gladstone Institutes, San Francisco, CA (United States)

Viruses and virally derived particles have the intrinsic capacity to deliver molecules to cells, but the difficulty of readily altering cell-type selectivity has hindered their use for therapeutic delivery. Here, we show that cell surface marker recognition by antibody fragments displayed on membrane-derived particles encapsulating CRISPR–Cas9 protein and guide RNA can deliver genome editing tools to specific cells. Compared to conventional vectors like adeno-associated virus that rely on evolved capsid tropisms to deliver virally encoded cargo, these Cas9-packaging enveloped delivery vehicles (Cas9-EDVs) leverage predictable antibody–antigen interactions to transiently deliver genome editing machinery selectively to cells of interest. Antibody-targeted Cas9-EDVs preferentially confer genome editing in cognate target cells over bystander cells in mixed populations, both ex vivo and in vivo. By using multiplexed targeting molecules to direct delivery to human T cells, Cas9-EDVs enable the generation of genome-edited chimeric antigen receptor T cells in humanized mice, establishing a programmable delivery modality with the potential for widespread therapeutic utility.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); Natural Sciences and Engineering Research Council of Canada (NSERC); USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2337619

Journal Information:: Nature Biotechnology, Journal Name: Nature Biotechnology Vol. 42; ISSN 1087-0156

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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immunotherapy
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Title: In vivo human T cell engineering with enveloped delivery vehicles

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