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Enhancing extracellular vesicle cargo loading and functional delivery by engineering protein-lipid interactions

Author

Listed:
  • Justin A. Peruzzi

    (Northwestern University
    Northwestern University)

  • Taylor F. Gunnels

    (Northwestern University
    Northwestern University)

  • Hailey I. Edelstein

    (Northwestern University
    Northwestern University)

  • Peilong Lu

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Westlake Institute for Advanced Study)

  • David Baker

    (University of Washington
    University of Washington
    University of Washington)

  • Joshua N. Leonard

    (Northwestern University
    Northwestern University
    Northwestern University
    Northwestern University)

  • Neha P. Kamat

    (Northwestern University
    Northwestern University
    Northwestern University
    Northwestern University)

Abstract

Naturally generated lipid nanoparticles termed extracellular vesicles (EVs) hold significant promise as engineerable therapeutic delivery vehicles. However, active loading of protein cargo into EVs in a manner that is useful for delivery remains a challenge. Here, we demonstrate that by rationally designing proteins to traffic to the plasma membrane and associate with lipid rafts, we can enhance loading of protein cargo into EVs for a set of structurally diverse transmembrane and peripheral membrane proteins. We then demonstrate the capacity of select lipid tags to mediate increased EV loading and functional delivery of an engineered transcription factor to modulate gene expression in target cells. We envision that this technology could be leveraged to develop new EV-based therapeutics that deliver a wide array of macromolecular cargo.

Suggested Citation

  • Justin A. Peruzzi & Taylor F. Gunnels & Hailey I. Edelstein & Peilong Lu & David Baker & Joshua N. Leonard & Neha P. Kamat, 2024. "Enhancing extracellular vesicle cargo loading and functional delivery by engineering protein-lipid interactions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49678-z
    DOI: 10.1038/s41467-024-49678-z
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    References listed on IDEAS

    as
    1. Joseph H. Lorent & Blanca Diaz-Rohrer & Xubo Lin & Kevin Spring & Alemayehu A. Gorfe & Kandice R. Levental & Ilya Levental, 2017. "Structural determinants and functional consequences of protein affinity for membrane rafts," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    2. Chunfu Xu & Peilong Lu & Tamer M. Gamal El-Din & Xue Y. Pei & Matthew C. Johnson & Atsuko Uyeda & Matthew J. Bick & Qi Xu & Daohua Jiang & Hua Bai & Gabriella Reggiano & Yang Hsia & T J Brunette & Jia, 2020. "Computational design of transmembrane pores," Nature, Nature, vol. 585(7823), pages 129-134, September.
    3. Justin A. Peruzzi & Jan Steinkühler & Timothy Q. Vu & Taylor F. Gunnels & Vivian T. Hu & Peilong Lu & David Baker & Neha P. Kamat, 2024. "Hydrophobic mismatch drives self-organization of designer proteins into synthetic membranes," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Ryosuke Kojima & Daniel Bojar & Giorgio Rizzi & Ghislaine Charpin-El Hamri & Marie Daoud El-Baba & Pratik Saxena & Simon Ausländer & Kelly R. Tan & Martin Fussenegger, 2018. "Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    5. Surya Shrivastava & Roslyn M. Ray & Leo Holguin & Lilliana Echavarria & Nicole Grepo & Tristan A. Scott & John Burnett & Kevin V. Morris, 2021. "Exosome-mediated stable epigenetic repression of HIV-1," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    6. Patrick S. Donahue & Joseph W. Draut & Joseph J. Muldoon & Hailey I. Edelstein & Neda Bagheri & Joshua N. Leonard, 2020. "The COMET toolkit for composing customizable genetic programs in mammalian cells," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
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