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Genetically targeted chemical assembly

Nature Reviews Bioengineering volume 2, pages 82–94 (2024)Cite this article

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Abstract

Cell type-specific interfaces within living animals will be invaluable for achieving communication with identifiable cells over the long term, enabling applications across many scientific and medical fields. However, biological tissues exhibit complex and dynamic organization properties that pose serious challenges for chronic cell-specific interfacing. A new technology, combining chemistry and molecular biology, has emerged to address this challenge: genetically targeted chemical assembly (GTCA), in which specific cells are genetically programmed (even in wild-type or non-transgenic animals, including mammals) to chemically construct non-biological structures. Here, we discuss recent progress in genetically targeted construction of materials and outline opportunities that may expand the GTCA toolbox, including specific chemical processes involving novel monomers, catalysts and reaction regimes both de cellula (from the cell) and ad cellula (towards the cell); different GTCA-compatible reaction conditions with a focus on light-based patterning; and potential applications of GTCA in research and clinical settings.

Key points

  • Genetically targeted chemical assembly (GTCA) uses cell-specific genetic information to guide the assembly of functional materials in situ.

  • The GTCA toolbox can be expanded through specific chemical processes involving novel monomers, catalysts and reaction conditions or regimes.

  • GTCA allows both building structures from the targeted cell membrane (de cellula) and an alternative approach (ad cellula) for cell-specific attachment of partially synthesized materials.

  • Different GTCA-compatible reaction conditions can be imposed through modulation of light, pH, heat and other signals.

  • The broad GTCA concept can be applied for both fundamental research and the treatment of diseases in the central and peripheral nervous systems.

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Fig. 1: Genetically targeted chemical assembly of polymers de cellula on living cellular membranes: localization and polymerization schemata for pyrrole derivatives.
Fig. 2: Genetically enabled ad cellula conjugation of pre-synthesized materials on living cell membranes.
Fig. 3: Genetically targeted reaction conditions.
Fig. 4: Applications from central to peripheral nervous systems.

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Acknowledgements

The Keck Foundation supported development of light-initiated polymerization and applications in living neural networks. The National Science Foundation Future Manufacturing Program grant (award no. 2037164) supported chemical method development for genetically targeted chemical assembly (GTCA). Both grants were awarded to K.D. and Z.B. based on the original GTCA concept and next-generation methods described previously15. A.Z. acknowledges support from the American Heart Association (AHA) (award no. 23POST1018301). K.Y.L. acknowledges support from the Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program (NIH 5T32GM120007) and Bio-X Bowes Fellowship. Z.B. is a Chan Zuckerberg Biohub San Francisco investigator.

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Authors and Affiliations

  1. Department of Chemical Engineering, Stanford University, Stanford, CA, USA

    Anqi Zhang, Yuanwen Jiang & Zhenan Bao

  2. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Anqi Zhang & Karl Deisseroth

  3. Department of Chemistry, Stanford University, Stanford, CA, USA

    Kang Yong Loh

  4. Sarafan Chemistry, Engineering and Medicine for Human Health (ChEM-H) Institute, Stanford University, Stanford, CA, USA

    Kang Yong Loh

  5. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Karl Deisseroth

  6. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

    Karl Deisseroth

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  1. Anqi Zhang
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  2. Yuanwen Jiang
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  3. Kang Yong Loh
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  4. Zhenan Bao
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Contributions

A.Z., Z.B. and K.D. wrote the manuscript with edits from all authors. Z.B. and K.D. supervised all aspects of the work. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Zhenan Bao or Karl Deisseroth.

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Competing interests

All techniques and protocols are freely available to the academic community, and the authors provide free training in genetically targeted chemical assembly (GTCA) methods at Stanford in workshops that can be accessed for registration online (https://web.stanford.edu/group/dlab/optogenetics/oil.html). Z.B. and K.D. are co-inventors of the GTCA concept used here, in intellectual property filed and owned by Stanford University.

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Nature Reviews Bioengineering thanks Itaru Imayoshi, Brian Timko and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Zhang, A., Jiang, Y., Loh, K.Y. et al. Genetically targeted chemical assembly. Nat Rev Bioeng 2, 82–94 (2024). https://doi.org/10.1038/s44222-023-00110-z

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