Biomaterials can improve the safety and presentation of therapeutic agents for effective immunotherapy, and a high level of control over surface functionalization is essential for immune cell modulation. Here, we developed biocompatible immune cell-engaging particles (ICEp) that use synthetic short DNA as scaffolds for efficient and tunable protein loading. To improve the safety of chimeric antigen receptor (CAR) T cell therapies, micrometre-sized ICEp were injected intratumorally to present a priming signal for systemically administered AND-gate CAR-T cells. Locally retained ICEp presenting a high density of priming antigens activated CAR T cells, driving local tumour clearance while sparing uninjected tumours in immunodeficient mice. The ratiometric control of costimulatory ligands (anti-CD3 and anti-CD28 antibodies) and the surface presentation of a cytokine (IL-2) on ICEp were shown to substantially impact human primary T cell activation phenotypes. This modular and versatile biomaterial functionalization platform can provide new opportunities for immunotherapies.
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The original data of the gel electrophoresis images are publicly available at Dryad Digital Repository (https://doi.org/10.7272/Q6CC0XXJ). Any other raw data that support the plots within this paper are available from the authors upon reasonable request.
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Portions of this work were supported by the National Institutes of Health Grants 5T32GM008155 and 1U54CA244438. We thank Z. Gartner for DNA synthesis, S. Habelitz for DLS analysis, C. Hayzelden for SEM imaging, B. Hann for IVIS imaging, K. Shokat for Tecan plate reader and C. Zamecnik and A. Li for helpful discussion. X.H. was supported by a UCSF programme for breakthrough biomedical research (PBBR) postdoctoral independent research grant and a Li foundation fellowship. J.Z.W. was supported by a Genentech Pre-Doctoral Fellowship. R.C. was supported by National Institute of General Medical Sciences (NIGMS) Medical Scientist Training Program no. T32GM007618.
T.A.D., W.A.L., X.H., J.Z.W. and R.C. are inventors of pending patents related to the technology described in the manuscript. Z.L., C.E.B., R.H.-L., I.S., E.G., D.M.P., W.Y. and K.T.R. declare no competing interests.
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Huang, X., Williams, J.Z., Chang, R. et al. DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation. Nat. Nanotechnol. 16, 214–223 (2021). https://doi.org/10.1038/s41565-020-00813-z