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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.
Understanding principles that govern protein association with extracellular vesicles should expand their potential as a therapeutic modality. Here, the authors show that by localizing proteins to the plasma membrane and lipid rafts, a variety of proteins can be preferentially loaded into extracellular vesicles.
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1 Northwestern University, Department of Chemical and Biological Engineering, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Center for Synthetic Biology, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507)
2 Northwestern University, Center for Synthetic Biology, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Department of Biomedical Engineering, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507)
3 Westlake University, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Hangzhou, China (GRID:grid.494629.4) (ISNI:0000 0004 8008 9315); Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China (GRID:grid.494629.4) (ISNI:0000 0004 8008 9315); Westlake Institute for Advanced Study, Institute of Biology, Hangzhou, China (GRID:grid.494629.4) (ISNI:0000 0004 8008 9315)
4 University of Washington, Department of Biochemistry, Seattle, USA (GRID:grid.34477.33) (ISNI:0000 0001 2298 6657); University of Washington, Institute for Protein Design, Seattle, USA (GRID:grid.34477.33) (ISNI:0000 0001 2298 6657); University of Washington, Howard Hughes Medical Institute, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657)
5 Northwestern University, Department of Chemical and Biological Engineering, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Department of Biomedical Engineering, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Chemistry of Life Processes Institute, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Member, Robert H. Lurie Comprehensive Cancer Center, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Interdisciplinary Biological Sciences Program, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507)
6 Northwestern University, Center for Synthetic Biology, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Department of Biomedical Engineering, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Chemistry of Life Processes Institute, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Member, Robert H. Lurie Comprehensive Cancer Center, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507); Northwestern University, Interdisciplinary Biological Sciences Program, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507)