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Cell-targetable DNA nanocapsules for spatiotemporal release of caged bioactive small molecules

Nature Nanotechnology volume 12, pages 1183–1189 (2017)Cite this article

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Abstract

Achieving triggered release of small molecules with spatial and temporal precision at designated cells within an organism remains a challenge. By combining a cell-targetable, icosahedral DNA-nanocapsule loaded with photoresponsive polymers, we show cytosolic delivery of small molecules with the spatial resolution of single endosomes in specific cells in Caenorhabditis elegans. Our technology can report on the extent of small molecules released after photoactivation as well as pinpoint the location at which uncaging of the molecules occurred. We apply this technology to release dehydroepiandrosterone (DHEA), a neurosteroid that promotes neurogenesis and neuron survival, and determined the timescale of neuronal activation by DHEA, using light-induced release of DHEA from targeted DNA nanocapsules. Importantly, sequestration inside the DNA capsule prevents photocaged DHEA from activating neurons prematurely. Our methodology can in principle be generalized to diverse neurostimulatory molecules.

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Figure 1: Light-stimulated release of small-molecule payloads from a DNA nanocapsule.
Figure 2: Light-triggered release of small molecules from chemically modified dextrans.
Figure 3: Light-stimulated cytosolic delivery of a targeted payload in live cells and in vivo.
Figure 4: Light-triggered activation of neurons by photocaged DHEA.

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Acknowledgements

The authors thank the Integrated Light Microscopy facility at the University of Chicago. K.X. acknowledges a summer research fellowship from the Department of Chemistry, University of Chicago and S.S.S. acknowledges the Cure Alzheimer's Fund. This work was supported by Human Frontier Science Program Research grant no. RGP0029/2014, the National Center for Advancing Translational Sciences of the National Institutes of Health through grant no. UL1 TR000430, Materials Research Science and Engineering Center grant no. DMR-1420709, and UChicago start-up funds to Y.K. Y.K. is a Brain Research Foundation Fellow.

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Author notes

  1. Kasturi Chakraborty, Kangni Xiao and Myles R. Minter: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, 60637, Illinois, USA

    Aneesh T. Veetil, Kasturi Chakraborty, Kangni Xiao & Yamuna Krishnan

  2. Grossman Institute of Neuroscience, Quantitative Biology and Human Behaviour, University of Chicago, Chicago, 60637, Illinois, USA

    Aneesh T. Veetil, Kasturi Chakraborty, Kangni Xiao, Myles R. Minter, Sangram S. Sisodia & Yamuna Krishnan

  3. Department of Neurobiology, University of Chicago, Chicago, 60637, Illinois, USA

    Myles R. Minter & Sangram S. Sisodia

  4. The Microbiome Center, University of Chicago, Chicago, 60637, Illinois, USA

    Myles R. Minter & Sangram S. Sisodia

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  1. Aneesh T. Veetil
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Contributions

A.T.V., K.X. and M.R.M. contributed reagents and performed experiments. K.C. provided expertise in C. elegans. A.T.V., K.C. and Y.K. analysed the data. A.T.V. and Y.K. conceived the project and wrote the paper. All authors discussed the results and gave input on the manuscript.

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Correspondence to Yamuna Krishnan.

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Veetil, A., Chakraborty, K., Xiao, K. et al. Cell-targetable DNA nanocapsules for spatiotemporal release of caged bioactive small molecules. Nature Nanotech 12, 1183–1189 (2017). https://doi.org/10.1038/nnano.2017.159

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