title: Design and application of multifunctional DNA nanocarriers for therapeutic delivery.
abstract: The unique programmability of nucleic acids offers versatility and flexibility in the creation of self-assembled DNA nanostructures. To date, many three-dimensional DNA architectures of varying sizes and shapes have been precisely formed. Their biocompatibility, biodegradability and high intrinsic stability in physiological environments emphasize their emerging use as carriers for drug and gene delivery. Furthermore, DNA nanocarriers have been shown to enter cells efficiently and without the aid of transfection reagents. A key strength of DNA nanocarriers over other delivery systems is their modularity and their ability to control the spatial distribution of cargoes and ligands. Optimizing DNA nanocarrier properties to dictate their localization, uptake and intracellular trafficking is also possible. This review presents design considerations for DNA nanocarriers and examples of their use in the context of therapeutic delivery applications. The assembly of DNA nanocarriers and approaches for loading and releasing cargo are described. The stability and safety of DNA nanocarriers are also discussed, with particular attention to the in vivo physiological environment. Mechanisms of cellular uptake and intracellular trafficking are examined, and the paper concludes with strategies to enhance the delivery efficiency of DNA nanocarriers.
authors.affiliation: Department of Polymer Science and Engineering, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: P
authors.initials: P
authors.lastname: Charoenphol
authors.affiliation: Department of Polymer Science and Engineering, University of Massachusetts, Amherst, MA 01003, USA. Electronic address: bermudez@polysci.umass.edu.
authors.forename: H
authors.initials: H
authors.lastname: Bermudez
mesh_terms: D000818:Animals; D004247:DNA / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004705:Endocytosis; D018014:Gene Transfer Techniques; D006801:Humans; D049329:Nanostructures / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D004247:DNA
keywords: Aptamers; DNA; Drug delivery; Nanotechnology; Self-assembly
references.citation: Nat Mater. 2008 Jul;7(7):588-95
references.pmid: 18500347
references.citation: Chem Commun (Camb). 2009 Dec 7;(45):7036-8
references.pmid: 19904386
references.citation: Proc Natl Acad Sci U S A. 1989 May;86(10):3474-8
references.pmid: 2726730
references.citation: Nat Med. 2003 Oct;9(10):1262-3
references.pmid: 14520374
references.citation: J Control Release. 2000 Mar 1;65(1-2):271-84
references.pmid: 10699287
references.citation: Toxicol Sci. 2009 Jul;110(1):138-55
references.pmid: 19414515
references.citation: Chembiochem. 2003 Oct 6;4(10):928-35
references.pmid: 14523910
references.citation: J Am Chem Soc. 2012 Oct 10;134(40):16488-91
references.pmid: 23020598
references.citation: Biochemistry. 1993 May 11;32(18):4855-61
references.pmid: 8490026
references.citation: Proc Natl Acad Sci U S A. 1989 Sep;86(17):6454-8
references.pmid: 2549537
references.citation: Nat Nanotechnol. 2007 Dec;2(12):751-60
references.pmid: 18654426
references.citation: Angew Chem Int Ed Engl. 2004 Jul 5;43(27):3550-3
references.pmid: 15293242
references.citation: Nano Lett. 2011 Apr 13;11(4):1477-82
references.pmid: 21366226
references.citation: Science. 2005 Dec 9;310(5754):1661-5
references.pmid: 16339440
references.citation: Nano Lett. 2009 Jan;9(1):308-11
references.pmid: 19099465
references.citation: Mol Pharmacol. 1994 May;45(5):932-43
references.pmid: 8190109
references.citation: Annu Rev Biochem. 1998;67:199-225
references.pmid: 9759488
references.citation: Chem Soc Rev. 2006 Nov;35(11):1111-21
references.pmid: 17057840
references.citation: Oligonucleotides. 2008 Dec;18(4):305-19
references.pmid: 19025401
references.citation: Eur J Pharm Biopharm. 2008 Mar;68(3):676-87
references.pmid: 17945472
references.citation: Chem Commun (Camb). 2013 Mar 11;49(20):2010-2
references.pmid: 23380739
references.citation: Langmuir. 2005 Mar 15;21(6):2605-13
references.pmid: 15752059
references.citation: Nat Commun. 2011 Jun 07;2:339
references.pmid: 21654639
references.citation: J Comput Chem. 2011 Jan 15;32(1):170-3
references.pmid: 20645303
references.citation: Interface Focus. 2011 Oct 6;1(5):702-24
references.pmid: 23050076
references.citation: Chem Commun (Camb). 2010 Feb 28;46(8):1209-11
references.pmid: 20449252
references.citation: ACS Nano. 2008 Jun;2(6):1213-8
references.pmid: 19206339
references.citation: Clin Exp Immunol. 1984 Apr;56(1):185-92
references.pmid: 6609032
references.citation: J Gene Med. 2011 Nov;13(11):602-10
references.pmid: 22015632
references.citation: Nature. 2008 Mar 13;452(7184):198-201
references.pmid: 18337818
references.citation: Adv Drug Deliv Rev. 2008 Aug 17;60(11):1278-88
references.pmid: 18514969
references.citation: Nucleic Acids Res. 2012 Apr;40(7):2862-8
references.pmid: 22156372
references.citation: Cancer Res. 1995 Sep 1;55(17):3752-6
references.pmid: 7641188
references.citation: Biophys J. 2003 Jun;84(6):3829-37
references.pmid: 12770888
references.citation: Mol Pharm. 2009 May-Jun;6(3):686-95
references.pmid: 19397332
references.citation: Biochemistry. 1994 Apr 5;33(13):3794-800
references.pmid: 8142381
references.citation: ACS Nano. 2011 Nov 22;5(11):8783-9
references.pmid: 21988181
references.citation: J Am Chem Soc. 2010 Aug 4;132(30):10212-4
references.pmid: 20662492
references.citation: Chem Commun (Camb). 2010 Mar 21;46(11):1866-8
references.pmid: 20198235
references.citation: Nat Rev Drug Discov. 2005 Jul;4(7):581-93
references.pmid: 16052241
references.citation: Angew Chem Int Ed Engl. 2012 Apr 2;51(14):3382-5
references.pmid: 22374892
references.citation: Nat Rev Drug Discov. 2008 Sep;7(9):771-82
references.pmid: 18758474
references.citation: Angew Chem Int Ed Engl. 2006 Nov 13;45(44):7414-7
references.pmid: 17086586
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4607-12
references.pmid: 9539785
references.citation: Atherosclerosis. 2005 Sep;182(1):1-15
references.pmid: 15904923
references.citation: Nucleic Acids Res. 2009 Feb;37(3):866-76
references.pmid: 19103663
references.citation: Pharm Res. 2001 Jan;18(1):67-74
references.pmid: 11336355
references.citation: Mol Genet Metab. 2003 Sep-Oct;80(1-2):148-58
references.pmid: 14567964
references.citation: Nano Lett. 2009 Jun;9(6):2445-7
references.pmid: 19419184
references.citation: AAPS J. 2005 Apr 08;7(1):E61-77
references.pmid: 16146351
references.citation: J Am Chem Soc. 2012 Feb 15;134(6):2888-91
references.pmid: 22283197
references.citation: Annu Rev Biochem. 1998;67:99-134
references.pmid: 9759484
references.citation: Curr Opin Struct Biol. 2000 Jun;10(3):326-31
references.pmid: 10851195
references.citation: Chem Commun (Camb). 2013 Apr 11;49(28):2906-8
references.pmid: 23459629
references.citation: Nat Chem. 2010 Apr;2(4):319-28
references.pmid: 21124515
references.citation: Nat Rev Mol Cell Biol. 2008 Aug;9(8):655-62
references.pmid: 18545270
references.citation: Cancer Res. 2010 Nov 1;70(21):8617-29
references.pmid: 20861190
references.citation: J Am Chem Soc. 2012 Aug 15;134(32):13396-403
references.pmid: 22803823
references.citation: N Engl J Med. 2003 Sep 4;349(10):969-74
references.pmid: 12954746
references.citation: Nat Rev Drug Discov. 2011 Jul 01;10(7):521-35
references.pmid: 21720407
references.citation: Nat Nanotechnol. 2007 Apr;2(4):249-55
references.pmid: 18654271
references.citation: Cell. 2006 Feb 24;124(4):729-40
references.pmid: 16497584
references.citation: Nat Rev Genet. 2007 Aug;8(8):573-87
references.pmid: 17607305
references.citation: Antisense Res Dev. 1991 Summer;1(2):153-60
references.pmid: 1841657
references.citation: ACS Nano. 2011 Aug 23;5(8):6156-63
references.pmid: 21732610
references.citation: Eur Urol. 2000 Aug;38(2):208-17
references.pmid: 10895014
references.citation: Nat Nanotechnol. 2009 May;4(5):325-30
references.pmid: 19421220
references.citation: Chem Commun (Camb). 2006 Mar 7;(9):968-9
references.pmid: 16491178
references.citation: Pharmacol Rev. 2006 Mar;58(1):32-45
references.pmid: 16507881
references.citation: J Phys Chem B. 2010 Dec 23;114(50):16929-35
references.pmid: 21090816
references.citation: Int J Hypertens. 2010 Aug 17;2010:646929
references.pmid: 20981357
references.citation: Nat Nanotechnol. 2012 Jun 03;7(6):389-93
references.pmid: 22659608
references.citation: Annu Rev Biochem. 2010;79:65-87
references.pmid: 20222824
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4930-4
references.pmid: 16549762
references.citation: Annu Rev Cell Dev Biol. 1996;12:575-625
references.pmid: 8970738
references.citation: Vaccine. 2005 Jan 4;23(7):890-6
references.pmid: 15603889
references.citation: Nat Rev Drug Discov. 2010 Aug;9(8):615-27
references.pmid: 20616808
references.citation: ACS Nano. 2009 Feb 24;3(2):425-33
references.pmid: 19236081
references.citation: Science. 2012 Feb 17;335(6070):831-4
references.pmid: 22344439
references.citation: Chem Commun (Camb). 2012 Dec 25;48(99):12118-20
references.pmid: 23143043
references.citation: J Biol Chem. 2011 Mar 11;286(10):8231-8239
references.pmid: 21205827
references.citation: Nature. 2000 Aug 10;406(6796):605-8
references.pmid: 10949296
references.citation: Biotechnol Bioeng. 2000 Mar 5;67(5):598-606
references.pmid: 10649234
references.citation: Nat Biotechnol. 2005 Jun;23(6):709-17
references.pmid: 15908939
references.citation: Mol Pharmacol. 1992 Jun;41(6):1023-33
references.pmid: 1352033
references.citation: Annu Rev Biophys Biomol Struct. 1998;27:225-48
references.pmid: 9646868
references.citation: Nature. 2009 May 7;459(7243):73-6
references.pmid: 19424153
references.citation: Small. 2011 May 23;7(10):1322-37
references.pmid: 21520409
references.citation: Small. 2011 Dec 16;7(24):3529-35
references.pmid: 22025353
references.citation: Pharm Res. 1995 Jun;12(6):825-30
references.pmid: 7667185
references.citation: Angew Chem Int Ed Engl. 2007;46(46):8819-22
references.pmid: 17935099
references.citation: Proc Natl Acad Sci U S A. 2013 May 7;110(19):7625-30
references.pmid: 23613589
references.citation: Expert Opin Drug Deliv. 2010 Aug;7(8):895-913
references.pmid: 20629604
references.citation: Angew Chem Int Ed Engl. 2006 Mar 13;45(12):1942-5
references.pmid: 16482506
references.citation: Nat Rev Clin Oncol. 2010 Nov;7(11):653-64
references.pmid: 20838415
references.citation: Angew Chem Int Ed Engl. 2010 Apr 26;49(19):3280-94
references.pmid: 20401880
references.citation: Nucleic Acids Res. 1988 Apr 25;16(8):3209-21
references.pmid: 2836790
references.citation: Small. 2010 Sep 6;6(17):1854-8
references.pmid: 20715076
references.citation: Bioorg Med Chem. 2007 Feb 1;15(3):1275-9
references.pmid: 17142047
references.citation: Angew Chem Int Ed Engl. 2006 Mar 13;45(12):1856-76
references.pmid: 16470892
references.citation: Nature. 2009 May 21;459(7245):414-8
references.pmid: 19458720
references.citation: Antisense Nucleic Acid Drug Dev. 2002 Apr;12(2):51-63
references.pmid: 12074365
references.citation: Biomacromolecules. 2008 Nov;9(11):3039-43
references.pmid: 18821795
references.citation: Bioelectrochemistry. 2002 Nov;58(1):53-64
references.pmid: 12401571
references.citation: J Am Chem Soc. 2011 Jun 22;133(24):9254-7
references.pmid: 21630678
references.citation: Atherosclerosis. 2011 Aug;217(2):364-70
references.pmid: 21601207
references.citation: J Phys Chem B. 2008 Dec 4;112(48):15283-94
references.pmid: 18989907
references.citation: Nucleic Acids Res. 1997 Aug 15;25(16):3290-6
references.pmid: 9241243
references.citation: ACS Nano. 2011 Dec 27;5(12):9696-702
references.pmid: 22092186
references.citation: ACS Nano. 2011 Jul 26;5(7):5427-32
references.pmid: 21696187
references.citation: Nat Commun. 2011 Jun 07;2:340
references.pmid: 21654640
references.citation: Small. 2012 May 7;8(9):1320-5
references.pmid: 22354792
references.citation: AAPS J. 2009 Mar;11(1):13-22
references.pmid: 19125334
references.citation: J Biomol Struct Dyn. 1990 Dec;8(3):573-81
references.pmid: 2100519
references.citation: Nano Lett. 2006 Apr;6(4):662-8
references.pmid: 16608261
references.citation: J Control Release. 2006 Aug 10;114(1):100-9
references.pmid: 16831482