title: Engineering nanolayered particles for modular drug delivery.
abstract: Layer-by-layer (LbL) based self-assembly of nanoparticles is an emerging and powerful method to develop multifunctional and tissue responsive nanomedicines for a broad range of diseases. This unique assembly technique is able to confer a high degree of modularity, versatility, and compositional heterogeneity to nanoparticles via the sequential deposition of alternately charged polyelectrolytes onto a colloidal template. LbL assembly can provide added functionality by directly incorporating a range of functional materials within the multilayers including nucleic acids, synthetic polymers, polypeptides, polysaccharides, and functional proteins. These materials can be used to generate hierarchically complex, heterogeneous thin films on an extensive range of both traditional and novel nanoscale colloidal templates, providing the opportunity to engineer highly precise systems capable of performing the numerous tasks required for systemic drug delivery. In this review, we will discuss the recent advancements towards the development of LbL nanoparticles for drug delivery and diagnostic applications, with a special emphasis on the incorporation of biostability, active targeting, desirable drug release kinetics, and combination therapies into LbL nanomaterials. In addition to these topics, we will touch upon the next steps for the translation of these systems towards the clinic.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Santiago
authors.initials: S
authors.lastname: Correa
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Dreaden
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Gu
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA 02139, United States. Electronic address: hammond@mit.edu.
authors.forename: Paula T
authors.initials: PT
authors.lastname: Hammond
mesh_terms: D000818:Animals; D004337:Drug Carriers / Q000737:chemistry*; D018014:Gene Transfer Techniques; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods*; D000068936:Theranostic Nanomedicine / Q000379:methods*
chemical_list: D004337:Drug Carriers; D004364:Pharmaceutical Preparations
keywords: Active targeting; Biomaterials; Clinical translation; Colloid chemistry; Combination therapy; Controlled release; Diagnostics; Drug delivery; Gene delivery; Layer-by-layer; Nanoparticles; Polymer engineering; Scalable synthesis; Shelf life; Theranostics
references.citation: Langmuir. 2015 Jul 14;31(27):7601-8
references.pmid: 26114616
references.citation: Biotechnol Adv. 2012 Nov-Dec;30(6):1551-61
references.pmid: 22561011
references.citation: Biomater Sci. 2014 Jul 3;2(7):996-1006
references.pmid: 32481973
references.citation: Adv Drug Deliv Rev. 2011 Aug 14;63(9):822-36
references.pmid: 21684313
references.citation: Macromol Biosci. 2009 Apr 8;9(4):326-35
references.pmid: 19089871
references.citation: Adv Drug Deliv Rev. 2003 Feb 24;55(3):329-47
references.pmid: 12628320
references.citation: Cell Transplant. 2010;19(1):55-65
references.pmid: 20370988
references.citation: Adv Mater. 2013 Oct 25;25(40):5767-71
references.pmid: 23946245
references.citation: J Am Chem Soc. 2010 Nov 17;132(45):15881-3
references.pmid: 20977221
references.citation: Adv Mater. 2010 Oct 8;22(38):4293-7
references.pmid: 20564713
references.citation: ACS Nano. 2010 Sep 28;4(9):5505-11
references.pmid: 20707386
references.citation: Sci Signal. 2014 May 13;7(325):ra44
references.pmid: 24825919
references.citation: ACS Nano. 2008 May;2(5):814-20
references.pmid: 19206476
references.citation: ACS Nano. 2013 Jan 22;7(1):522-30
references.pmid: 23234433
references.citation: Small. 2012 Aug 20;8(16):2585-94
references.pmid: 22674655
references.citation: Nanoscale. 2013 Jan 7;5(1):23-37
references.pmid: 23135546
references.citation: Nanoscale. 2015 Apr 21;7(15):6703-11
references.pmid: 25798789
references.citation: Chem Soc Rev. 2011 Jan;40(1):19-29
references.pmid: 20882254
references.citation: Small. 2012 Sep 24;8(18):2819-22
references.pmid: 22777707
references.citation: Science. 1996 Feb 23;271(5252):1116-20
references.pmid: 8599088
references.citation: ACS Nano. 2013 May 28;7(5):4135-50
references.pmid: 23634842
references.citation: Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13948-53
references.pmid: 25214538
references.citation: Nanotechnology. 2015 May 22;26(20):205101
references.pmid: 25927227
references.citation: Nat Mater. 2012 Feb 26;11(4):316-22
references.pmid: 22367004
references.citation: Adv Drug Deliv Rev. 2011 Aug 14;63(9):772-88
references.pmid: 21554908
references.citation: Langmuir. 2005 Jun 21;21(13):6086-92
references.pmid: 15952864
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14265-70
references.pmid: 18809927
references.citation: Adv Healthc Mater. 2015 Sep 16;4(13):1972-81
references.pmid: 26138108
references.citation: Small. 2007 Aug;3(8):1341-6
references.pmid: 17566138
references.citation: ACS Nano. 2015 Jun 23;9(6):6465-77
references.pmid: 26035231
references.citation: Langmuir. 2015 Aug 25;31(33):9054-60
references.pmid: 26267807
references.citation: Biomaterials. 2009 Oct;30(29):5639-48
references.pmid: 19646751
references.citation: Soft Matter. 2012 Jan 1;8(36):9418-9427
references.pmid: 23144650
references.citation: ACS Nano. 2011 Dec 27;5(12):9583-91
references.pmid: 22059733
references.citation: Biomacromolecules. 2011 Apr 11;12(4):1283-9
references.pmid: 21375235
references.citation: Adv Mater. 2012 Apr 17;24(15):1987-93
references.pmid: 22422477
references.citation: Chem Commun (Camb). 2011 Jan 7;47(1):550-2
references.pmid: 21103586
references.citation: Macromol Biosci. 2006 Feb 10;6(2):153-60
references.pmid: 16456874
references.citation: J Am Chem Soc. 2007 Jul 25;129(29):8962-3
references.pmid: 17602632
references.citation: Langmuir. 2006 Sep 12;22(19):8178-85
references.pmid: 16952259
references.citation: ACS Nano. 2014 Oct 28;8(10):9767-80
references.pmid: 25198246
references.citation: Nano Lett. 2006 Mar;6(3):530-6
references.pmid: 16522057
references.citation: Clin Cancer Res. 2012 Apr 15;18(8):2316-25
references.pmid: 22261800
references.citation: PLoS One. 2013 Sep 10;8(9):e74905
references.pmid: 24040360
references.citation: J Biol Chem. 1962 Jun;237:1992-2000
references.pmid: 13891108
references.citation: Langmuir. 2005 May 10;21(10):4262-5
references.pmid: 16032831
references.citation: Adv Mater. 2016 Feb 10;28(6):1295-301
references.pmid: 26390356
references.citation: ACS Nano. 2012 Jan 24;6(1):771-81
references.pmid: 22136582
references.citation: Acta Biomater. 2010 Aug;6(8):3092-100
references.pmid: 20197128
references.citation: ACS Nano. 2011 Aug 23;5(8):6138-47
references.pmid: 21739990
references.citation: ACS Nano. 2015 Sep 22;9(9):9078-86
references.pmid: 26266334
references.citation: Langmuir. 2009 Sep 1;25(17):10020-5
references.pmid: 19705896
references.citation: Nano Lett. 2011 May 11;11(5):2096-103
references.pmid: 21524115
references.citation: Vaccine. 2011 Jan 10;29(3):558-69
references.pmid: 20951665
references.citation: Biomaterials. 2010 Apr;31(12):3287-95
references.pmid: 20132982
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10207-10212
references.pmid: 16801543
references.citation: Nat Commun. 2014 Jun 20;5:4206
references.pmid: 24947309
references.citation: Angew Chem Int Ed Engl. 2009;48(45):8485-9
references.pmid: 19810070
references.citation: Langmuir. 2011 Jun 21;27(12):7868-76
references.pmid: 21574582
references.citation: Langmuir. 2005 Jan 4;21(1):403-10
references.pmid: 15620331
references.citation: Cancer Lett. 2008 Sep 28;269(1):57-66
references.pmid: 18541363
references.citation: J Phys Chem Lett. 2015 Sep 17;6(18):3621-5
references.pmid: 26722732
references.citation: Lab Chip. 2008 Dec;8(12):2182-7
references.pmid: 19023485
references.citation: Angew Chem Int Ed Engl. 2015 Jan 19;54(4):1365-8
references.pmid: 25483403
references.citation: Langmuir. 2010 Jun 1;26(11):7679-81
references.pmid: 20459072
references.citation: ACS Nano. 2014 Aug 26;8(8):8374-82
references.pmid: 25100313
references.citation: ACS Nano. 2013 Nov 26;7(11):9571-84
references.pmid: 24144228
references.citation: Angew Chem Int Ed Engl. 2012 Sep 24;51(39):9818-21
references.pmid: 22951900
references.citation: J Control Release. 2006 Mar 10;111(1-2):235-46
references.pmid: 16466824
references.citation: Lab Chip. 2011 Mar 21;11(6):1030-5
references.pmid: 21218225
references.citation: Arch Toxicol. 2014 Jul;88(7):1391-417
references.pmid: 24894431
references.citation: Biomacromolecules. 2001 Fall;2(3):921-6
references.pmid: 11710050
references.citation: Nature. 2014 Mar 27;507(7493):519-22
references.pmid: 24531764
references.citation: Chem Sci. 2015 Jun 1;6(6):3505-3514
references.pmid: 28706710
references.citation: Nat Med. 2012 Dec;18(12):1841-6
references.pmid: 23160236
references.citation: Biomaterials. 2009 Oct;30(28):5178-86
references.pmid: 19545890
references.citation: Adv Funct Mater. 2016 Feb 16;26(7):991-1003
references.pmid: 27134622
references.citation: ACS Nano. 2012 Aug 28;6(8):7340-51
references.pmid: 22838646
references.citation: Small. 2012 Dec 21;8(24):3847-56
references.pmid: 22911477
references.citation: J Am Chem Soc. 2012 Jun 27;134(25):10664-9
references.pmid: 22667448
references.citation: Acta Biomater. 2015 Oct;25:194-204
references.pmid: 26193000
references.citation: Acc Chem Res. 2012 Nov 20;45(11):1854-65
references.pmid: 22546051
references.citation: Acta Biomater. 2010 Jan;6(1):210-7
references.pmid: 19531385
references.citation: Acta Biomater. 2014 Dec;10(12):5116-5127
references.pmid: 25169256
references.citation: Adv Healthc Mater. 2014 Jun;3(6):867-75
references.pmid: 24124132
references.citation: ACS Nano. 2011 Jun 28;5(6):4284-92
references.pmid: 21513353
references.citation: J Am Chem Soc. 2004 Mar 24;126(11):3374-5
references.pmid: 15025435
references.citation: Invest Radiol. 2009 Jun;44(6):336-42
references.pmid: 19661843
references.citation: J Colloid Interface Sci. 2010 May 15;345(2):241-7
references.pmid: 20227712
references.citation: Nano Lett. 2009 May;9(5):2059-64
references.pmid: 19331425
references.citation: Nanomedicine (Lond). 2012 May;7(5):619-22
references.pmid: 22630144
references.citation: Clin Cancer Res. 2015 Oct 1;21(19):4410-9
references.pmid: 26034127
references.citation: Chem Soc Rev. 2014 May 21;43(10):3453-79
references.pmid: 24549278
references.citation: Langmuir. 2009 Dec 15;25(24):14079-85
references.pmid: 20560555
references.citation: Adv Mater. 2013 Sep 14;25(34):4707-13
references.pmid: 23813892
references.citation: Nat Mater. 2013 Apr;12(4):367-76
references.pmid: 23353628
references.citation: J Colloid Interface Sci. 1970 Mar;32(3):456-63
references.pmid: 5417531
references.citation: Biomaterials. 2013 Jul;34(21):5328-35
references.pmid: 23618629
references.citation: Chem Soc Rev. 2011 Jul;40(7):3391-404
references.pmid: 21629885
references.citation: Expert Rev Mol Diagn. 2012 Nov;12(8):857-70
references.pmid: 23249203
references.citation: Chem Rev. 2015 Oct 14;115(19):10816-906
references.pmid: 25997028
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3137-42
references.pmid: 22315430
references.citation: ACS Appl Mater Interfaces. 2015 Jun 10;7(22):11972-83
references.pmid: 25985366
references.citation: Small. 2014 May 14;10(9):1790-8
references.pmid: 24510544
references.citation: ACS Nano. 2009 Jul 28;3(7):1877-85
references.pmid: 19534472
references.citation: Biomacromolecules. 2010 Aug 9;11(8):2053-9
references.pmid: 20690713
references.citation: Angew Chem Int Ed Engl. 1998 Sep 4;37(16):2201-2205
references.pmid: 29711461
references.citation: J Am Chem Soc. 2005 Feb 16;127(6):1626-7
references.pmid: 15700982
references.citation: Ther Deliv. 2012 Apr;3(4):457-78
references.pmid: 22834077
references.citation: Nanoscale. 2014 Aug 7;6(15):9198-205
references.pmid: 24980695
references.citation: Nano Lett. 2009 Feb;9(2):636-42
references.pmid: 19170551
references.citation: J Control Release. 2008 Jun 24;128(3):255-60
references.pmid: 18479772
references.citation: J Am Chem Soc. 2011 Mar 2;133(8):2525-34
references.pmid: 21288025
references.citation: Nano Lett. 2009 May;9(5):1909-15
references.pmid: 19344179
references.citation: Int J Nanomedicine. 2012;7:925-39
references.pmid: 22393290
references.citation: ACS Nano. 2012 Apr 24;6(4):3189-95
references.pmid: 22439823
references.citation: J Biomed Mater Res A. 2016 Mar;104(3):707-713
references.pmid: 26519869
references.citation: Adv Healthc Mater. 2014 Oct;3(10):1629-37
references.pmid: 24692076
references.citation: Biomacromolecules. 2010 Nov 8;11(11):3136-43
references.pmid: 20942396
references.citation: J Phys Chem B. 2005 Apr 14;109(14):6845-8
references.pmid: 16851770
references.citation: Langmuir. 2011 Feb 1;27(3):1212-7
references.pmid: 21190345
references.citation: Chem Mater. 2012 Mar 13;24(5):812-827
references.pmid: 22919122
references.citation: Biomaterials. 2010 Aug;31(23):6039-49
references.pmid: 20471081
references.citation: Biomaterials. 2013 Jul;34(21):5172-80
references.pmid: 23591397
references.citation: Chem Soc Rev. 2012 Sep 21;41(18):6103-24
references.pmid: 22695830
references.citation: Adv Mater. 2010 Jan 26;22(4):441-67
references.pmid: 20217734
references.citation: Small. 2009 Mar;5(6):701-8
references.pmid: 19226599
references.citation: Biomaterials. 2012 Mar;33(7):2215-22
references.pmid: 22169825
references.citation: Acta Biomater. 2015 Jan;11:393-403
references.pmid: 25246314
references.citation: Nucleic Acids Res. 2016 Jan 29;44(2):545-57
references.pmid: 26704983
references.citation: J Control Release. 2014 Dec 10;195:99-109
references.pmid: 25078552
references.citation: Biomaterials. 2008 Oct;29(30):4045-55
references.pmid: 18675454
references.citation: Biomaterials. 2014 Mar;35(9):3110-20
references.pmid: 24411335
references.citation: Pharm Res. 2012 Oct;29(10):2902-11
references.pmid: 22723122
references.citation: ACS Nano. 2011 Dec 27;5(12):9788-98
references.pmid: 22070571
references.citation: Phys Chem Chem Phys. 2011 May 21;13(19):9014-9
references.pmid: 21442095
references.citation: ACS Nano. 2010 Aug 24;4(8):4539-50
references.pmid: 20731437
references.citation: Langmuir. 2011 Feb 15;27(4):1275-80
references.pmid: 21126103
references.citation: Nucleic Acids Res. 1999 Aug 1;27(15):3090-5
references.pmid: 10454604
references.citation: Nat Protoc. 2013 Oct;8(10):2033-44
references.pmid: 24071909
references.citation: ACS Nano. 2012 Mar 27;6(3):2136-49
references.pmid: 22303914
references.citation: J Colloid Interface Sci. 2008 Aug;324(1-2):47-54
references.pmid: 18514212
references.citation: Biomaterials. 2010 Feb;31(5):998-1006
references.pmid: 19850333
references.citation: Angew Chem Int Ed Engl. 2016 Mar 1;55(10):3347-51
references.pmid: 26695874
references.citation: Adv Healthc Mater. 2015 Apr 22;4(6):811-30
references.pmid: 25627563
references.citation: Small. 2015 Feb 25;11(8):952-62
references.pmid: 25330768
references.citation: J Phys Chem B. 2015 Aug 20;119(33):10554-65
references.pmid: 26061703
references.citation: J Control Release. 2012 Feb 28;158(1):2-14
references.pmid: 21925219
references.citation: Int J Pharm. 2014 Apr 25;465(1-2):218-27
references.pmid: 24508806
references.citation: Langmuir. 2014 Jul 29;30(29):8931-7
references.pmid: 24998291
references.citation: Mater Sci Eng C Mater Biol Appl. 2014 Jan 1;34:384-92
references.pmid: 24268273
references.citation: Circ Cardiovasc Imaging. 2014 May;7(3):517-25
references.pmid: 24657826
references.citation: Chem Soc Rev. 2012 Apr 7;41(7):2740-79
references.pmid: 22109657
references.citation: Expert Opin Drug Deliv. 2010 Apr;7(4):535-50
references.pmid: 20201712
references.citation: Angew Chem Int Ed Engl. 2005 Sep 19;44(37):6054-7
references.pmid: 16118828
references.citation: J Colloid Interface Sci. 2015 Jun 15;448:197-207
references.pmid: 25734222
references.citation: Adv Mater. 2013 Jun 18;25(23):3144-76
references.pmid: 23681931
references.citation: Langmuir. 2014 Aug 26;30(33):10028-34
references.pmid: 25113552
references.citation: J Am Chem Soc. 2013 Feb 20;135(7):2427-30
references.pmid: 23363241
references.citation: Small. 2011 Feb 7;7(3):364-70
references.pmid: 21294265
references.citation: Small. 2014 Apr 24;10(8):1623-33
references.pmid: 24851252
references.citation: ACS Appl Mater Interfaces. 2015 Apr 22;7(15):7891-900
references.pmid: 25815610
references.citation: Biomacromolecules. 2014 Apr 14;15(4):1382-9
references.pmid: 24598017
references.citation: Langmuir. 2008 Mar 4;24(5):1778-89
references.pmid: 18225923
references.citation: Nat Mater. 2009 Jul;8(7):543-57
references.pmid: 19525947
references.citation: Angew Chem Int Ed Engl. 2013 Jun 17;52(25):6455-8
references.pmid: 23657949
references.citation: Science. 1998 Nov 6;282(5391):1111-4
references.pmid: 9804547
references.citation: Nano Lett. 2006 Apr;6(4):662-8
references.pmid: 16608261
references.citation: Adv Drug Deliv Rev. 2011 Aug 14;63(9):847-64
references.pmid: 21620912