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

Justin A. Peruzzi, Taylor F. Gunnels, Hailey I. Edelstein, Peilong Lu, David Baker, Joshua N. Leonard () and Neha P. Kamat ()
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Justin A. Peruzzi: Northwestern University
Taylor F. Gunnels: Northwestern University
Hailey I. Edelstein: Northwestern University
Peilong Lu: Westlake University
David Baker: University of Washington
Joshua N. Leonard: Northwestern University
Neha P. Kamat: Northwestern University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49678-z

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