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Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy

Nature Biotechnology volume 33, pages 64–72 (2015)Cite this article

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Abstract

Implanting materials in the body to program host immune cells is a promising alternative to transplantation of cells manipulated ex vivo to direct an immune response, but doing so requires a surgical procedure. Here we demonstrate that high-aspect-ratio, mesoporous silica rods (MSRs) injected with a needle spontaneously assemble in vivo to form macroporous structures that provide a 3D cellular microenvironment for host immune cells. In mice, substantial numbers of dendritic cells are recruited to the pores between the scaffold rods. The recruitment of dendritic cells and their subsequent homing to lymph nodes can be modulated by sustained release of inflammatory signals and adjuvants from the scaffold. Moreover, injection of an MSR-based vaccine formulation enhances systemic helper T cells TH1 and TH2 serum antibody and cytotoxic T-cell levels compared to bolus controls. These findings suggest that injectable MSRs may serve as a multifunctional vaccine platform to modulate host immune cell function and provoke adaptive immune responses.

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Figure 1: A schematic representation of in vivo spontaneous assembly of MSRs and recruitment of host cells for maturation.
Figure 2: Subcutaneous injection of blank MSRs results in their spontaneous assembly in vivo, and substantial numbers of cells are recruited into interparticle pores of assembled MSRs.
Figure 3: Cytokine, PAMP and model antigen are released from MSR scaffold in sustained manner in vitro and in vivo.
Figure 4: Vaccine formulation consisting of MSRs loaded with GM-CSF, CpG and OVA is able to recruit dendritic cells, program them with antigen and PAMP, and enhance their trafficking to the dLN to exert systemic effects.
Figure 5: MSR vaccine generates potent humoral and cellular immune responses against a model antigen, OVA.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) (1R01EB015498), the National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP), the Wyss Institute for Biologically Inspired Engineering at Harvard University, and National Research Foundation (NRF) grants (2012R1A1A1042735, 2010-0027955) funded by the National Research Foundation under the Ministry of Science, ICT & Future Planning, Korea. We also thank Dana-Farber/Harvard Cancer Center (DF/HCC) Research Pathology Core and R. Bronson for the examination of the histology slides and J. Weaver from the Wyss Institute of Biologically Inspired Engineering for his help with scanning electron microscopy (SEM). Lastly, we thank R. Betensky from the Department of Biostatistics, Harvard School of Public Health and the Harvard Catalyst for her help with statistical analysis; Harvard Catalyst is supported, in part, by the NIH (UL1 TR001102).

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Author notes

  1. Jaeyun Kim and Weiwei Aileen Li: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA

    Jaeyun Kim, Weiwei Aileen Li, Catia S Verbeke & David J Mooney

  2. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA

    Jaeyun Kim, Weiwei Aileen Li, Sarah A Lewin, Catia S Verbeke & David J Mooney

  3. School of Chemical Engineering, Sungkyunkwan University, Suwon, Korea

    Jaeyun Kim & Youngjin Choi

  4. Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Glenn Dranoff

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Contributions

J.K., W.A.L. and D.J.M. conceived and designed the experiments. J.K., W.A.L., Y.C., S.A.L. and C.S.V. performed the experiments. J.K., W.A.L., G.D. and D.J.M. analyzed the data. J.K., W.A.L. and D.J.M. wrote the manuscript. All authors discussed the results and commented on the manuscript. J.K. and W.A.L. contributed equally to this work. The principal investigator is D.J.M.

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Correspondence to David J Mooney.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14 (PDF 1774 kb)

Supplementary Video 1

Z-stack of confocal images of sectioned nodule retrieved at day 7 post-injection. The injected MSRs were labeled with AF488 and load with GM-CSF (1 μg). The cross-section was stained with DAPI and phalloidin. (MOV 7043 kb)

Supplementary Video 2

Z-stack of confocal images of sectioned nodule retrieved at day 28 post-injection. The injected MSRs were labeled with AF488 and load with GM-CSF (1 μg). The cross-section was stained with DAPI and phalloidin. (MOV 2628 kb)

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Kim, J., Li, W., Choi, Y. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat Biotechnol 33, 64–72 (2015). https://doi.org/10.1038/nbt.3071

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