Abstract
The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8+ T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated in this study, including source data for the figures, are available via figshare at https://doi.org/10.6084/m9.figshare.25928314 (ref. 67). Source data are provided with this paper.
Code availability
scRNAseq data generated from this study, the processed cell matrix, data tables (such as expression values) and metadata are available from the Gene Expression Omnibus database via the accession code GSE242531.
Change history
15 April 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41551-025-01386-9
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Acknowledgements
This work was supported in part by a UCLA Jonsson Comprehensive Cancer Center (JCCC) Seed Grant (to S.L. and L.Y.), a UCLA Broad Stem Cell Research Center (BSCRC) Innovation Award (to S.L.), a grant from the National Institutes of Health (NIH) (GM143485, to S.L.), a Discovery Stage Award from the California Institute for Regenerative Medicine (CIRM) (DISC2-14169, to S.L.) and an Ablon Scholars Award (to L.Y.). Y.-R.L. is a postdoctoral fellow supported by a UCLA Microbiology, Immunology, and Molecular Genetics M. John Pickett Post-Doctoral Fellow Award and a CIRM-BSCRC Postdoctoral Fellowship. E.Z. acknowledges the NIH/National Heart, Lung, and Blood Institute (NHLBI) T32HL144449. E.Z. and T.H. acknowledge the NIH/NHLBI R01HL129727 and NIH/NHLBI R01HL159970. We thank the UCLA Division of Laboratory Animal Medicine (DLAM) for providing animal support, the UCLA BSCRC Flow Cytometry Core Facility for providing cell sorting support, the UCLA TCGB facility for providing scRNAseq services, the UCLA Center for AIDS Research (CFAR) Virology Core for providing human PBMCs and the Advanced Light Microscopy/Spectroscopy Laboratory and the Leica Microsystems Center at the California NanoSystems Institute for supporting the image acquisition. We also thank the NIH Tetramer Facility for providing the tetramers, and the Christopher Seet Lab (UCLA) for providing the human Jurkat T-cell line and Jurkat NFAT-zsGreen reporter cell line used in this study.
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Contributions
Z. Liu, Y.-R.L., L.Y. and S.L. designed the experiments. Z. Liu, Y.-R.L., Yu Zhu, Y.Y., M.M.H.-S., E.Z., H.N., J.Z., X.G., Z. Li, K.-W.Y., Yichen Zhu and Y.F. performed the experiments. Z. Liu, Y.-R.L., Yu Zhu, E.Z., J. Shen and Y.Y. analysed the data. Z. Liu, Y.-R.L., Yu Zhu, Y.Y., E.Z., Y.W., T.H., W.Y., J. Soto, T.H., L.Y. and S.L. discussed and interpreted the results. Z. Liu, Y.-R.L., Yu Zhu, Y.Y., E.Z., L.Y. and S.L. wrote and revised the manuscript.
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Z. Liu, Y.-R.L., L.Y. and S.L. filed a patent application (PCT/US24/22516) on SynVAC as inventors. The other authors declare no competing interests.
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Nature Biomedical Engineering thanks Paolo Provenzano and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
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Supplementary Figures and Tables.
Supplementary Video 1
Microsphere fabrication.
Supplementary Video 2
Co-culture of SynVACs.
Supplementary Video 3
Co-culture of Dynabeads.
Source data
Source Data Fig. 6
Source data for tumour burden.
Source Data Fig. 7
Source data for tumour burden.
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Liu, Z., Li, YR., Yang, Y. et al. Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies. Nat. Biomed. Eng 8, 1615–1633 (2024). https://doi.org/10.1038/s41551-024-01272-w
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DOI: https://doi.org/10.1038/s41551-024-01272-w
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