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DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation

Abstract

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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Fig. 1: Polymeric micro-/nanoparticles with surface DNA scaffolds for protein presentation allow versatile modulation of immune cell therapies.
Fig. 2: DNA scaffolds enable efficient loading of multiple therapeutic proteins on particle surfaces at precisely tunable ratios.
Fig. 3: Compatibility of DNA-scaffolded PLGA particles for in vivo applications.
Fig. 4: Local activation of AND-gate CAR-T cell for tumour killing by intratumoral injection of ICEp presenting a priming antigen.
Fig. 5: ICEp, capable of versatile and precisely controlled modulatory signals, regulates T cell characteristics during ex vivo expansion.

Data availability

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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Acknowledgements

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.

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X.H., J.Z.W., R.C., K.T.R., W.A.L. and T.A.D. designed the experiments and interpreted the results. X.H., J.Z.W., R.C., Z.L., C.E.B., R.H.-L., I.S., E.G. and W.Y. performed the experiments, and D.M.P. contributed to material designs and synthesis. X.H. analysed the data and drafted the manuscript. X.H., J.Z.W., R.C., I.S., W.A.L. and T.A.D. edited the manuscript.

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Correspondence to Wendell A. Lim or Tejal A. Desai.

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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

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