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Nat. Biotechnol., 17 August 2026 | https://doi.org/10.1038/s41587-026-03258-2 Virus-like particles enable targeted gene engineering and pooled CRISPR screening in primary human myeloid cells

Hyuncheol Jung^1,2,3,27, Pascal Devant^1,27, Carter Ching², Mineto Ota^1,4,5, Emma Dann^1,4,5, Ronghui Zhu^1,4,5, Chandrima Modak^1,4,5, Ana Vasquez-Ibarra¹, Jennifer R. Hamilton^6,7,25, Zachary Steinhart^1,3, Wayne Ngo^6,8,9, Luis Sandoval², Jae Hyung Jung², Jae Hyun J. Lee^1,10, Da Xu7, Meirui An^11,12,13, Esha Urs², Peixin Amy Chen², Vincent Allain^1,2,26, Takuya Tada¹⁴, Luke A. Gilbert^15,16,17, Brian R. Shy^1,10,18, Jonathan K. Pritchard^4,5, James K. Nuñez^7,19, Nathaniel R. Landau¹⁴, David R. Liu^11,12,13, Justin Eyquem^{1,2,3,15,18,20,21}, Jennifer A. Doudna^{1,6,7,8,9,22,23,24}, Alexander Marson^{1,2,3,6,15,16,18,21} & Julia Carnevale^1,2,3,15,18

¹Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
²Department of Medicine, University of California, San Francisco, CA, USA.
³Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁴Department of Genetics, Stanford University, Stanford, CA, USA.
⁵Department of Biology, Stanford University, Stanford, CA, USA.
⁶Innovative Genomics Institute, University of California, Berkeley, CA, USA.
⁷Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁸Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
⁹California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA.
¹⁰Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
¹¹Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹²Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
¹³Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
¹⁴Department of Microbiology, NYU Grossman School of Medicine, New York, NY, USA.
¹⁵UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
¹⁶Arc Institute, Palo Alto, CA, USA.
¹⁷Department of Urology, University of California, San Francisco, CA, USA.
¹⁸Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA.
¹⁹Chan Zuckerberg Biohub San Francisco, San Francisco, CA, USA.
²⁰Institute for Human Genetics (IHG), University of California, San Francisco, CA, USA.
²¹Department of Microbiology and Immunology, University of California, San Francisco, CA, USA.
²²Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
²³Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
²⁴Department of Chemistry, University of California, Berkeley, CA, USA.
²⁵Present address: Azalea Therapeutics, Berkeley, CA, USA.
²⁶Present address: Hôpital Saint-Louis, Université Paris Cité, INSERM UMR1342, Paris, France.
²⁷These authors contributed equally: Hyuncheol Jung, Pascal Devant.

Corresponding authors
Correspondence to Alexander Marson or Julia Carnevale.

Abstract

Primary human myeloid cells hold promise for immunotherapies, yet efficient, scalable technologies for engineering and screening in these cells remain limited. Here we present a virus-like particle (VLP)-based toolkit that delivers diverse CRISPR editing modalities to human monocytes, macrophages and dendritic cells with high efficiency while preserving viability and innate immune responsiveness. VLP-mediated delivery of ribonucleoproteins supports gene knockout, base editing and epigenetic silencing. Combined with adeno-associated virus-mediated donor delivery, this approach enables site-specific integration of large DNA sequences by homology-directed repair. We developed SLICeVLP, which pairs sgRNA delivery by VPX-lentivirus with Cas9 protein delivery by engineered VLPs, and used it for pooled loss-of-function and Perturb-seq screens in human macrophages. We uncovered regulators of tumor necrosis factor (TNF) and CD80 expression, converging on TNFAIP3 as a central regulator of inflammatory polarization. TNFAIP3 ablation drove a proinflammatory state resistant to suppressive repolarization and enhanced cytotoxicity in chimeric antigen receptor macrophages. This system enables unbiased functional genomics in primary human myeloid cells, with implications for myeloid cell therapy design.

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