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Cell type-specific delivery by modular envelope design

Author

Listed:
  • Daniel Strebinger

    (Howard Hughes Medical Institute
    Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Chris J. Frangieh

    (Howard Hughes Medical Institute
    Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Mirco J. Friedrich

    (Howard Hughes Medical Institute
    Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Guilhem Faure

    (Howard Hughes Medical Institute
    Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Rhiannon K. Macrae

    (Howard Hughes Medical Institute
    Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Feng Zhang

    (Howard Hughes Medical Institute
    Broad Institute of MIT and Harvard
    McGovern Institute for Brain Research, Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of targetable delivery vectors. Enveloped delivery modalities use viral envelope proteins, which determine tropism and induce membrane fusion. Here we develop DIRECTED (Delivery to Intended REcipient Cells Through Envelope Design), a modular platform that consists of separate fusion and targeting components. To achieve high modularity and programmable cell type specificity, we develop multiple strategies to recruit or immobilize antibodies on the viral envelope, including a chimeric antibody binding protein and a SNAP-tag enabling the use of antibodies or other proteins as targeting molecules. Moreover, we show that fusogens from multiple viral families are compatible with DIRECTED and that DIRECTED components can target multiple delivery chassis (e.g., lentivirus and MMLV gag) to specific cell types, including primary human T cells in PBMCs and whole blood.

Suggested Citation

  • Daniel Strebinger & Chris J. Frangieh & Mirco J. Friedrich & Guilhem Faure & Rhiannon K. Macrae & Feng Zhang, 2023. "Cell type-specific delivery by modular envelope design," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40788-8
    DOI: 10.1038/s41467-023-40788-8
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