title: FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver.
abstract: Many aspects of intercellular communication are mediated through "sending" and "receiving" packets of information via the secretion and subsequent receptor-mediated detection of biomolecular species including cytokines, chemokines, and even metabolites. Recent evidence has now established a new modality of intercellular communication through which biomolecular species are exchanged between cells via extracellular lipid vesicles. A particularly important class of extracellular vesicles is exosomes, which is a term generally applied to biological nanovesicles ~30-200 nm in diameter. Exosomes form through invagination of endosomes to encapsulate cytoplasmic contents, and upon fusion of these multivesicular endosomes to the cell surface, exosomes are released to the extracellular space and transport mRNA, microRNA (miRNA) and proteins between cells. Importantly, exosome-mediated delivery of such cargo molecules results in functional modulation of the recipient cell, and such modulation is sufficiently potent to modulate disease processes in vivo. It is possible that such functional delivery of biomolecules indicates that exosomes utilize native mechanisms (e.g., for internalization and trafficking) that may be harnessed by using exosomes to deliver exogenous RNA for therapeutic applications. A complementary perspective is that understanding the mechanisms of exosome-mediated transport may provide opportunities for "reverse engineering" such mechanisms to improve the performance of synthetic delivery vehicles. In this review, we summarize recent progress in harnessing exosomes for therapeutic RNA delivery, discuss the potential for engineering exosomes to overcome delivery challenges and establish robust technology platforms, and describe both potential challenges and advantages of utilizing exosomes as RNA delivery vehicles.
authors.affiliation: Interdepartmental Biological Sciences Graduate Program, Northwestern University Evanston, IL 60208-3120, USA.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Marcus
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Leonard
keywords: cancer; exosome; extracellular vesicle; gene therapy; immunity; nanoparticle; siRNA delivery
references.citation: J Immunol. 2012 Jun 15;188(12):5954-61
references.pmid: 22573809
references.citation: Blood. 2010 Jan 21;115(3):696-705
references.pmid: 19903899
references.citation: Curr Protoc Cell Biol. 2006 Apr;Chapter 3:Unit 3.22
references.pmid: 18228490
references.citation: Nat Med. 2012 Jun;18(6):883-91
references.pmid: 22635005
references.citation: J Exp Med. 1996 Mar 1;183(3):1161-72
references.pmid: 8642258
references.citation: Sci Rep. 2013;3:1197
references.pmid: 23378928
references.citation: Blood. 2012 Jan 19;119(3):756-66
references.pmid: 22031862
references.citation: Nat Cell Biol. 2008 Dec;10(12):1470-6
references.pmid: 19011622
references.citation: Mol Ther. 2011 Feb;19(2):395-9
references.pmid: 21102562
references.citation: J Control Release. 2012 Jul 20;161(2):600-8
references.pmid: 22230342
references.citation: Mol Ther. 2006 Feb;13(2):289-300
references.pmid: 16275099
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10592-7
references.pmid: 12947040
references.citation: Nucleic Acids Res. 2012 Sep 1;40(17):e130
references.pmid: 22618874
references.citation: Nat Cell Biol. 2009 Sep;11(9):1143-9
references.pmid: 19684575
references.citation: J Immunol. 2005 May 15;174(10):6440-8
references.pmid: 15879146
references.citation: J Transl Med. 2005 Mar 02;3(1):10
references.pmid: 15740633
references.citation: J Transl Med. 2005 Feb 21;3(1):9
references.pmid: 15723705
references.citation: Circulation. 2012 Nov 27;126(22):2601-11
references.pmid: 23114789
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D1241-4
references.pmid: 21989406
references.citation: Commun Integr Biol. 2010 Sep;3(5):478-81
references.pmid: 21057646
references.citation: J Cell Sci. 2011 Feb 1;124(Pt 3):447-58
references.pmid: 21242314
references.citation: J Biol Chem. 2012 Feb 3;287(6):3842-9
references.pmid: 22057275
references.citation: J Biol Chem. 2011 Apr 22;286(16):14383-95
references.pmid: 21300796
references.citation: J Cell Mol Med. 2006 Apr-Jun;10(2):376-88
references.pmid: 16796806
references.citation: Vaccine. 2010 Aug 16;28(36):5785-93
references.pmid: 20615489
references.citation: Blood. 2004 Nov 15;104(10):3257-66
references.pmid: 15284116
references.citation: J Immunother. 2011 Nov-Dec;34(9):611-28
references.pmid: 21989410
references.citation: Cancer Res. 2008 Feb 15;68(4):1228-35
references.pmid: 18281500
references.citation: PLoS One. 2012;7(11):e49723
references.pmid: 23166755
references.citation: J Biol Chem. 2012 Jan 6;287(2):1397-405
references.pmid: 22123823
references.citation: PLoS One. 2012;7(8):e44045
references.pmid: 22952868
references.citation: Biochim Biophys Acta. 1981 Jul 6;645(1):63-70
references.pmid: 6266476
references.citation: Nat Med. 1998 May;4(5):594-600
references.pmid: 9585234
references.citation: J Biol Chem. 2010 Jun 4;285(23):17442-52
references.pmid: 20353945
references.citation: Nat Biotechnol. 2011 Apr;29(4):341-5
references.pmid: 21423189
references.citation: Blood. 2009 Mar 19;113(12):2673-83
references.pmid: 19176319
references.citation: Vaccine. 2011 Nov 21;29(50):9361-7
references.pmid: 22001882
references.citation: J Biol Chem. 1987 Jul 5;262(19):9412-20
references.pmid: 3597417
references.citation: J Biol Chem. 2009 Dec 4;284(49):34211-22
references.pmid: 19801663
references.citation: Nat Cell Biol. 2009 Sep;11(9):1150-6
references.pmid: 19684574
references.citation: J Cell Biol. 2013 Feb 18;200(4):373-83
references.pmid: 23420871
references.citation: J Immunol Methods. 2002 Dec 15;270(2):211-26
references.pmid: 12379326
references.citation: J Immunol. 2007 Aug 15;179(4):2242-9
references.pmid: 17675485
references.citation: Nat Cell Biol. 2012 Feb 12;14(3):249-56
references.pmid: 22327366
references.citation: Cancer Lett. 2012 Feb 1;315(1):28-37
references.pmid: 22055459
references.citation: J Immunol. 2001 Dec 15;167(12):6736-44
references.pmid: 11739488
references.citation: Biochem J. 2004 May 15;380(Pt 1):161-71
references.pmid: 14965343
references.citation: J Cell Biol. 2013 Feb 18;200(4):367-71
references.pmid: 23420870
references.citation: Mol Ther. 2009 May;17(5):767-77
references.pmid: 19277019
references.citation: J Immunol. 2006 Sep 15;177(6):3757-62
references.pmid: 16951336
references.citation: Mol Ther Nucleic Acids. 2012 Feb 07;1:e10
references.pmid: 23344721
references.citation: J Immunol. 2006 Feb 1;176(3):1534-42
references.pmid: 16424182
references.citation: Biochim Biophys Acta. 2012 Jul;1820(7):940-8
references.pmid: 22503788
references.citation: J Virol. 2009 Jan;83(2):512-21
references.pmid: 18987139
references.citation: J Immunol. 2012 Sep 15;189(6):2833-42
references.pmid: 22904309
references.citation: Mol Ther. 2010 Sep;18(9):1606-14
references.pmid: 20571541
references.citation: Adv Drug Deliv Rev. 2013 Mar;65(3):336-41
references.pmid: 22780955
references.citation: BMC Cancer. 2011 Mar 27;11:108
references.pmid: 21439085
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6328-33
references.pmid: 20304794
references.citation: Stem Cells. 2012 Jul;30(7):1556-64
references.pmid: 22605481
references.citation: Blood. 2010 Sep 30;116(13):2385-94
references.pmid: 20558614
references.citation: Biochim Biophys Acta. 2012 Aug;1826(1):103-11
references.pmid: 22503823
references.citation: Vaccine. 2008 Jul 4;26(29-30):3662-72
references.pmid: 18538453
references.citation: J Immunol. 2007 Oct 15;179(8):5024-32
references.pmid: 17911587
references.citation: Genes Dev. 2009 Aug 15;23(16):1971-9
references.pmid: 19684116
references.citation: Nat Protoc. 2012 Dec;7(12):2112-26
references.pmid: 23154783
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):738-43
references.pmid: 16407131
references.citation: Nat Rev Immunol. 2009 Aug;9(8):581-93
references.pmid: 19498381
references.citation: Stem Cell Res. 2013 May;10(3):301-12
references.pmid: 23399448
references.citation: PLoS One. 2012;7(4):e34653
references.pmid: 22506041
references.citation: Adv Drug Deliv Rev. 2011 Sep 16;63(12):1020-30
references.pmid: 21787819
references.citation: EMBO J. 2011 Aug 31;30(17):3481-500
references.pmid: 21878991
references.citation: Mol Ther. 2008 Apr;16(4):782-90
references.pmid: 18362931
references.citation: Biochim Biophys Acta. 1991 Jan 9;1061(1):56-64
references.pmid: 1995057
references.citation: Eur J Immunol. 2003 Feb;33(2):522-31
references.pmid: 12645951
references.citation: PLoS One. 2011;6(10):e25294
references.pmid: 22022385
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20370-5
references.pmid: 21059916
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15336-41
references.pmid: 21873242
references.citation: J Neural Transm (Vienna). 2010 Jan;117(1):1-4
references.pmid: 19680595
references.citation: Int J Nanomedicine. 2012;7:1525-41
references.pmid: 22619510
references.citation: Mol Ther. 2013 Jan;21(1):101-8
references.pmid: 22910294
references.citation: Methods Mol Biol. 2011;728:235-46
references.pmid: 21468952
references.citation: Nat Rev Drug Discov. 2010 Jan;9(1):29-42
references.pmid: 20043027
references.citation: J Immunol. 2010 Nov 1;185(9):5268-78
references.pmid: 20881190
references.citation: Mol Ther. 2013 Jan;21(1):185-91
references.pmid: 23032975
references.citation: J Immunol. 2001 Jan 15;166(2):868-76
references.pmid: 11145662