基于DNA纳米结构的siRNA输送体系的研究进展
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摘要
随着多个功能性核酸药物获得FDA的批准,基因治疗近年来取得了长足的进步,迸发了新的青春.小干扰核糖核酸(siRNA)是基因治疗的核心成员,siRNA的高效递送则是其临床转化的关键.不同于传统阳离子脂质体、聚合物等通过静电相互作用实现siRNA的负载压缩形成纳米递送体系,DNA纳米结构通过核酸亲和杂化作用负载功能性核酸,实现siRNA的递送和相应的基因治疗.本文简要回顾了siRNA在基因沉默过程中的功能和机制,介绍了DNA纳米结构作为载体用于功能性核酸递送的基本原理和优缺点,进而详述了几类具有特色的DNA纳米结构用于siRNA递送系统,最后探讨了现有技术存在的挑战,并对本领域的发展做了进一步展望.
With the approval of multiple nucleic acid drugs for clinic use by FDA, we witness a revival of gene therapy in recent years. As one of the most important drug candidates, small interfering ribonucleic acid(siRNA) plays an essential role in gene silencing. Although a large variety of siRNA delivery systems have been developed, lack of efficient way to deliver siR NA to target tissue remains as a hurdle that retards the translation of siRNA for clinic use. Different from traditional cationic liposome and polymer based nano-delivery systems that load and compress the siRNA by electrostatic interaction, self-assembled DNA nanostructures can be equipped with functional nucleic acids by DNA hybridization, which further serve as vehicles for siRNA delivery. In this mini-review, first we introduce the concept of RNA interference(RNAi) based gene silencing and emphasize the importance. It is well known that siRNA can disturb the process of translating, silence genes, and further inhibit the expression of corresponding proteins via RNAi. However, naked siRNA is not stable during the circulation. Besides that, it is difficult for siRNA itself to enter the cells, demanding proper gene vehicles to assist its cellular and systemic delivery. Unlike traditional cationic carriers that are usually toxic to cells, DNA nanostructures have been verified with excellent biocompatibility and biodegradability. Along with the rapid development of DNA nanotechnology and tremendous DNA-based nanostructures that have been assembled, more attentions have been paid on using DNA nanostructures as new carriers for siRNA delivery. Subsequently, we systematically summarize the recent progress of DNA-based siRNA delivery systems, including their designs, structures, functions, and various applications. For instance, DNA nanocage is one representative carrier used for siRNA delivery. Lee once assembled DNA tetrahedron with 6 siRNAs on each strut and folate ligands on its surface, achieving enhanced efficiency of siRNA delivery for both in vitro and in vivo. Sleiman group also reported a DNA "nanosuitcase" to encapsulate siRNA and release it upon specific trigger. By virtue of DNA origami, Ke et al. designed DNA nanoparticles to transport siRNA and further investigated the morphology influence on cellular uptake efficiency. Moreover, taking advantage of rolling-circle amplification(RCA) method, new DNA-based delivery systems with different shapes, including Y-DNA structure and periodic DNA nanoribbons, were developed for siRNA delivery. Except barely loading functional siRNA on DNA nanostructures, protecting siRNA from degradation in the new delivery systems is also important. Recently, we also reported a crosslinked DNA hydrogel platform for siRNA delivery, in which siRNA can embedded inside the nanogel to avoid the enzymatic degradation. Both in vivo and in vitro results revealed that the crosslinked nanogel had excellent delivery efficiency and antitumor effect in an siR NA-based therapy. Despite great advances have been achieved, several problems remain to be solved in using DNA nanostructure for siRNA delivery. Lastly, we discuss the main challenges in this field, including the stability, immunogenicity, targeting capability, cost of the delivery vehicles and make a brief prospect. Once these problems are nicely addressed, we believe that DNA-based gene vectors will take a huge step toward practical use in clinic.
With the approval of multiple nucleic acid drugs for clinic use by FDA, we witness a revival of gene therapy in recent years. As one of the most important drug candidates, small interfering ribonucleic acid(siRNA) plays an essential role in gene silencing. Although a large variety of siRNA delivery systems have been developed, lack of efficient way to deliver siR NA to target tissue remains as a hurdle that retards the translation of siRNA for clinic use. Different from traditional cationic liposome and polymer based nano-delivery systems that load and compress the siRNA by electrostatic interaction, self-assembled DNA nanostructures can be equipped with functional nucleic acids by DNA hybridization, which further serve as vehicles for siRNA delivery. In this mini-review, first we introduce the concept of RNA interference(RNAi) based gene silencing and emphasize the importance. It is well known that siRNA can disturb the process of translating, silence genes, and further inhibit the expression of corresponding proteins via RNAi. However, naked siRNA is not stable during the circulation. Besides that, it is difficult for siRNA itself to enter the cells, demanding proper gene vehicles to assist its cellular and systemic delivery. Unlike traditional cationic carriers that are usually toxic to cells, DNA nanostructures have been verified with excellent biocompatibility and biodegradability. Along with the rapid development of DNA nanotechnology and tremendous DNA-based nanostructures that have been assembled, more attentions have been paid on using DNA nanostructures as new carriers for siRNA delivery. Subsequently, we systematically summarize the recent progress of DNA-based siRNA delivery systems, including their designs, structures, functions, and various applications. For instance, DNA nanocage is one representative carrier used for siRNA delivery. Lee once assembled DNA tetrahedron with 6 siRNAs on each strut and folate ligands on its surface, achieving enhanced efficiency of siRNA delivery for both in vitro and in vivo. Sleiman group also reported a DNA "nanosuitcase" to encapsulate siRNA and release it upon specific trigger. By virtue of DNA origami, Ke et al. designed DNA nanoparticles to transport siRNA and further investigated the morphology influence on cellular uptake efficiency. Moreover, taking advantage of rolling-circle amplification(RCA) method, new DNA-based delivery systems with different shapes, including Y-DNA structure and periodic DNA nanoribbons, were developed for siRNA delivery. Except barely loading functional siRNA on DNA nanostructures, protecting siRNA from degradation in the new delivery systems is also important. Recently, we also reported a crosslinked DNA hydrogel platform for siRNA delivery, in which siRNA can embedded inside the nanogel to avoid the enzymatic degradation. Both in vivo and in vitro results revealed that the crosslinked nanogel had excellent delivery efficiency and antitumor effect in an siR NA-based therapy. Despite great advances have been achieved, several problems remain to be solved in using DNA nanostructure for siRNA delivery. Lastly, we discuss the main challenges in this field, including the stability, immunogenicity, targeting capability, cost of the delivery vehicles and make a brief prospect. Once these problems are nicely addressed, we believe that DNA-based gene vectors will take a huge step toward practical use in clinic.
引文
1 Castanotto D,Rossi J J.The promises and pitfalls of RNA-interference-based therapeutics.Nature,2009,457:426-433
2 Dogini D B,Pascoal V D A B,Avansini S H,et al.The new world of RNAs.Genet Mol Biol,2014,37:285-290
3 Fire A,Xu S Q,Montgomery M K,et al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.Nature,1998,391:806-811
4 Li J,Xue S,Mao Z W.Nanoparticle delivery systems for siRNA-based therapeutics.J Mater Chem B,2016,4:6620-6639
5 Gallas A,Alexander C,Davies M C,et al.Chemistry and formulations for siRNA therapeutics.Chem Soc Rev,2013,42:7983-7997
6 Jinek M,Doudna J A.A three-dimensional view of the molecular machinery of RNA interference.Nature,2009,457:405-412
7 Perkel J M.RNAi therapeutics:A two-year update.Science,2009,326:454-454
8 Elbashir S M,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature,2001,411:494-498
9 Rana T M.Illuminating the silence:Understanding the structure and function of small RNAs.Nat Rev Mol Cell Biol,2007,8:23-36
10 Dykxhoorn D M,Novina C D,Sharp P A.Killing the messenger:Short RNAs that silence gene expression.Nat Rev Mol Cell Biol,2003,4:457-467
11 Pai S I,Lin Y Y,Macaes B,et al.Prospects of RNA interference therapy for cancer.Gene Ther,2006,13:464-477
12 Patil V S,Zhou R,Rana T M.Gene regulation by non-coding RNAs.Crit Rev Biochem Mol Biol,2014,49:16-32
13 Resnier P,Montier T,Mathieu V,et al.A review of the current status of siRNA nanomedicines in the treatment of cancer.Biomaterials,2013,34:6429-6443
14 Lam J K W,Chow M Y T,Yu Z,et al.siRNA versus miRNA as therapeutics for gene silencing.Mol Ther Nucleic Acids,2015,4:252-272
15 Chakraborty C,Sharma A R,Sharma G,et al.Therapeutic miRNA and siRNA:Moving from bench to clinic as next generation medicine.Mol Ther Nucleic Acids,2017,8:132-143
16 Castanotto D,Bertrand E,Rossi J.Exogenous cellular delivery of ribozymes and ribozyme encoding DNAs.In:Turner P C,ed.Ribozyme Protocols.Totowa,NJ:Humana Press,1997,74.429-439
17 Guzman-Villanueva D,El-Sherbiny I M,Herrera-Ruiz D,et al.Formulation approaches to short interfering RNA and MicroRNA:Challenges and implications.J Pharm Sci,2012,101:4046-4066
18 Chen S H,Zhaori G.Potential clinical applications of siRNA technique:Benefits and limitations.Eur J Clin Invest,2011,41:221-232
19 Soutschek J,Akinc A,Bramlage B,et al.Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.Nature,2004,432:173-178
20 Zins K,Sioud M,Aharinejad S,et al.Modulating the tumor microenvironment with RNA interference as a cancer treatment strategy.Methods Mol Biol,2015,1218:143
21 Chithrani B D,Ghazani A A,Chan W C W.Size and shape dependence of nanoparticles on Cellular Uptake.Nano Lett,2006,668:662-668
22 Ma D.Enhancing endosomal escape for nanoparticle mediated siRNA delivery.Nanoscale,2014,6:6415-6425
23 Gish R G,Yuen M F,Chan H L,et al.Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent.Antiviral Res,2015,121:97-108
24 Zuckerman J E,Choi C H,Han H,et al.Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.Proc Natl Acad Sci USA,2012,109:3137-3142
25 Wu X R,Wu C W,Zhang C.Discrete DNA three-dimensional nanostructures:The synthesis and applications.Chin J Polym Sci,2017,35:1-24
26 Seeman N C.Nucleic acid junctions and lattices.J Theor Biol,1982,99:237-247
27 Kallenbach N R,Ma R I,Seeman N C.An Immobile nucleic acid junction constructed from oligonucleotides.Nature,1983,305:829-831
28 Chen J,Seeman N C.Synthesis from DNA of a molecule with the connectivity of a cube.Nature,1991,350:631-633
29 Seeman N C.DNA in a material world.Nature,2003,421:427-431
30 Jones M R,Seeman N C,Mirkin C A.Programmable materials and the nature of the DNA bond.Science,2015,347:840-851
31 Woo S,Rothemund P W.Programmable molecular recognition based on the geometry of DNA nanostructures.Nat Chem,2011,3:620-627
32 Millstone J E,Georganopoulou D G,Xu X,et al.DNA-Gold triangular nanoprism conjugates.Small,2010,4:2176-2180
33 Ouyang X,Li J,Liu H,et al.Rolling circle amplification-based DNA origami nanostructrures for intracellular delivery of immunostimulatory drugs.Small,2014,9:3082-3087
34 Tian C,Li X,Liu Z,et al.Directed self-assembly of DNA tiles into complex nanocages.Angew Chem Int Ed,2014,53:8041-8044
35 Han D,Pal S,Yang Y,et al.DNA gridiron nanostructures based on four-arm junctions.Science,2013,339:1412-1415
36 Zhang F,Jiang S,Wu S,et al.Complex wireframe DNA origami nanostructures with multi-arm junction vertices.Nat Nanotechnol,2015,10:779-784
37 And F A A,Sleiman H F.Modular access to structurally switchable 3D discrete DNA assemblies.J Am Chem Soc,2007,129:13376-13377
38 Zhang C,Macfarlane R J,Young K L,et al.A general approach to DNA-programmable atom equivalents.Nat Mater,2013,12:741-746
39 Benson E,Mohammed A,Gardell J,et al.DNA rendering of polyhedral meshes at the nanoscale.Nature,2015,523:441-444
40 Ke Y,Ong L L,Shih W M,et al.Three-Dimensional structures self-assembled from DNA bricks.Science,2012,338:1177-1183
41 He Y,Ye T,Su M,et al.Hierarchical self-assembly of DNA into symmetric supramolecular polyhedra.Nature,2008,452:198-201
42 Lee D S,Qian H,Tay C Y,et al.Cellular processing and destinies of artificial DNA nanostructures.Chem Soc Rev,2016,45:4199-4225
43 Petros R A,Desimone J M.Strategies in the design of nanoparticles for therapeutic applications.Nat Rev Drug Discovery,2010,9:615-627
44 Choi H S,Liu W,Liu F,et al.Design considerations for tumour-targeted nanoparticles.Nat Nanotechnol,2010,5:42-47
45 Davis M E,Chen Z G,Shin D M.Nanoparticle therapeutics:An emerging treatment modality for cancer.Nat Rev Drug Discovery,2008,7:771-782
46 Chou L Y T,Zagorovsky K,Chan W C W.DNA assembly of nanoparticle superstructures for controlled biological delivery and elimination.Nat Nanotechnol,2014,9:148-155
47 Keefe A D,Pai S,Ellington A.Aptamers as therapeutics.Nat Rev Drug Discovery,2010,9:537-550
48 Kozlov M M,Mcmahon H T,Chernomordik L V.Protein-driven membrane stresses in fusion and fission.Trends Biochem Sci,2010,35:699-706
49 Hu Q,Li H,Wang L,et al.DNA nanotechnology-enabled drug delivery systems.Chem Rev,2018,doi:10.1021/acs.chemrev.7b00663
50 Hu Q,Wang S,Wang L,et al.DNA nanostructure-based systems for intelligent delivery of therapeutic oligonucleotides.Adv Healthcare Mater,2018,7:1701153
51 Bujold K E,Lacroix A,Sleiman H F.DNA nanostructures at the interface with biology.Chem,2018,4:495-521
52 Wang P,Meyer T A,Pan V,et al.The beauty and utility of DNA origami.Chem,2017,2:359-382
53 Pinheiro A V,Han D,Shih W M,et al.Challenges and opportunities for structural DNA nanotechnology.Nat Nanotechnol,2011,6:763-772
54 Juliano R L.The delivery of therapeutic oligonucleotides.Nucleic Acids Res,2016,44:6518-6548
55 Panyam J,Labhasetwar V.Biodegradable nanoparticles for drug and gene delivery to cells and tissue.Adv Drug Delivery Rev,2012,64:61-71
56 Jensen S A,Day E S,Ko C H,et al.Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma.Sci Transl Med,2013,5:1-12
57 Chao J,Liu H,Su S,et al.Structural DNA nanotechnology for intelligent drug delivery.Small,2015,10:4626-4635
58 Peer D,Karp J M,Hong S,et al.Nanocarriers as an emerging platform for cancer therapy.Nat Nanotechnol,2007,2:751-760
59 Afonin K A,Viard M,Martins A N,et al.Activation of different split functionalities on re-association of RNA-DNA hybrids.Nat Nanotechnol,2013,8:296-304
60 Lee J B,Hong J,Bonner D K,et al.Self-assembled RNA interference microsponges for efficient siRNA delivery.Nat Mater,2012,11:316-322
61 Choi C H,Hao L,Narayan S P,et al.Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates.Proc Natl Acad Sci USA,2013,110:7625-7630
62 Liang L,Li J,Li Q,et al.Single-particle tracking and modulation of cell entry pathways of a tetrahedral DNA nanostructure in live cells.Angew Chem Int Ed,2014,53:7745-7750
63 Lee H,Lyttonjean A K R,Chen Y,et al.Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery.Nat Nanotechnol,2013,7:389-393
64 Bujold K E,Hsu J C,Sleiman H F.Optimized DNA“Nanosuitcases”for encapsulation and conditional release of siRNA.J Am Chem Soc,2016,138:14030-14038
65 Lacroix A,Edwardson T G W,Hancock M A,et al.Development of DNA nanostructures for high affinity binding to human serum albumin.J Am Chem Soc,2017,139:7355-7362
66 Rahman M A,Wang P,Zhao Z,et al.Systemic delivery of Bc12-targeting siRNA by DNA nanoparticles suppresses cancer cell growth.Angew Chem Int Ed,2017,56:16023-16027
67 Hong C A,Jang B,Jeong E H,et al.Self-assembled DNA nanostructures prepared by rolling circle amplification for the delivery of siRNA conjugates.Chem Commun,2014,50:13049-13051
68 Chen G,Liu D,He C,et al.Enzymatic synthesis of periodic DNA nanoribbons for intracellular pH sensing and gene silencing.J Am Chem Soc,2015,137:3844-3851
69 Ren K,Liu Y,Wu J,et al.A DNA dual lock-and-key strategy for cell-subtype-specific siRNA delivery.Nat Commun,2016,7:13580
70 Ruan W,Zheng M,An Y,et al.DNA nanoclew templated spherical nucleic acids for siRNA delivery.Chem Commun,2018,54:3609-3612
71 Nuhn L,Hirsch M,Krieg B,et al.Cationic nanohydrogel particles as potential siRNA carriers for cellular delivery.ACS Nano,2012,6:2198-2214
72 Dahlman J E,Barnes C,Khan O F,et al.In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight.Nat Nanotechnol,2014,9:648-655
73 Li J,Zheng C,Cansiz S,et al.Self-assembly of DNA nanohydrogels with controllable size and stimuli-responsive property for targeted gene regulation therapy.J Am Chem Soc,2015,137:1412-1415
74 Ding F,Mou Q,Ma Y,et al.Crosslinked nucleic acid nanogel for effective siRNA delivery and antitumor therapy.Angew Chem Int Ed,2018,57:3064-3068
75 You Z,Qian H,Wang C,et al.Regulation of vascular smooth muscle cell autophagy by DNA nanotube-conjugated mTOR siRNA.Biomaterials,2015,67:137-150
76 Wang Y,You Z,Du J,et al.Self-assembled triangular DNA nanoparticles are an efficient system for gene delivery.J Control Release,2016,233:126-135
77 Ryou S M,Kim S,Jang H H,et al.Delivery of shRNA using gold nanoparticle-DNA oligonucleotide conjugates as a universal carrier.Biochem Biophys Res Commun,2010,398:542-546
78 Luo M,Wang H,Wang Z,et al.A STING-activating nanovaccine for cancer immunotherapy.Nat Nanotechnol,2017,12:648-654
2 Dogini D B,Pascoal V D A B,Avansini S H,et al.The new world of RNAs.Genet Mol Biol,2014,37:285-290
3 Fire A,Xu S Q,Montgomery M K,et al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.Nature,1998,391:806-811
4 Li J,Xue S,Mao Z W.Nanoparticle delivery systems for siRNA-based therapeutics.J Mater Chem B,2016,4:6620-6639
5 Gallas A,Alexander C,Davies M C,et al.Chemistry and formulations for siRNA therapeutics.Chem Soc Rev,2013,42:7983-7997
6 Jinek M,Doudna J A.A three-dimensional view of the molecular machinery of RNA interference.Nature,2009,457:405-412
7 Perkel J M.RNAi therapeutics:A two-year update.Science,2009,326:454-454
8 Elbashir S M,Harborth J,Lendeckel W,et al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature,2001,411:494-498
9 Rana T M.Illuminating the silence:Understanding the structure and function of small RNAs.Nat Rev Mol Cell Biol,2007,8:23-36
10 Dykxhoorn D M,Novina C D,Sharp P A.Killing the messenger:Short RNAs that silence gene expression.Nat Rev Mol Cell Biol,2003,4:457-467
11 Pai S I,Lin Y Y,Macaes B,et al.Prospects of RNA interference therapy for cancer.Gene Ther,2006,13:464-477
12 Patil V S,Zhou R,Rana T M.Gene regulation by non-coding RNAs.Crit Rev Biochem Mol Biol,2014,49:16-32
13 Resnier P,Montier T,Mathieu V,et al.A review of the current status of siRNA nanomedicines in the treatment of cancer.Biomaterials,2013,34:6429-6443
14 Lam J K W,Chow M Y T,Yu Z,et al.siRNA versus miRNA as therapeutics for gene silencing.Mol Ther Nucleic Acids,2015,4:252-272
15 Chakraborty C,Sharma A R,Sharma G,et al.Therapeutic miRNA and siRNA:Moving from bench to clinic as next generation medicine.Mol Ther Nucleic Acids,2017,8:132-143
16 Castanotto D,Bertrand E,Rossi J.Exogenous cellular delivery of ribozymes and ribozyme encoding DNAs.In:Turner P C,ed.Ribozyme Protocols.Totowa,NJ:Humana Press,1997,74.429-439
17 Guzman-Villanueva D,El-Sherbiny I M,Herrera-Ruiz D,et al.Formulation approaches to short interfering RNA and MicroRNA:Challenges and implications.J Pharm Sci,2012,101:4046-4066
18 Chen S H,Zhaori G.Potential clinical applications of siRNA technique:Benefits and limitations.Eur J Clin Invest,2011,41:221-232
19 Soutschek J,Akinc A,Bramlage B,et al.Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.Nature,2004,432:173-178
20 Zins K,Sioud M,Aharinejad S,et al.Modulating the tumor microenvironment with RNA interference as a cancer treatment strategy.Methods Mol Biol,2015,1218:143
21 Chithrani B D,Ghazani A A,Chan W C W.Size and shape dependence of nanoparticles on Cellular Uptake.Nano Lett,2006,668:662-668
22 Ma D.Enhancing endosomal escape for nanoparticle mediated siRNA delivery.Nanoscale,2014,6:6415-6425
23 Gish R G,Yuen M F,Chan H L,et al.Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent.Antiviral Res,2015,121:97-108
24 Zuckerman J E,Choi C H,Han H,et al.Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.Proc Natl Acad Sci USA,2012,109:3137-3142
25 Wu X R,Wu C W,Zhang C.Discrete DNA three-dimensional nanostructures:The synthesis and applications.Chin J Polym Sci,2017,35:1-24
26 Seeman N C.Nucleic acid junctions and lattices.J Theor Biol,1982,99:237-247
27 Kallenbach N R,Ma R I,Seeman N C.An Immobile nucleic acid junction constructed from oligonucleotides.Nature,1983,305:829-831
28 Chen J,Seeman N C.Synthesis from DNA of a molecule with the connectivity of a cube.Nature,1991,350:631-633
29 Seeman N C.DNA in a material world.Nature,2003,421:427-431
30 Jones M R,Seeman N C,Mirkin C A.Programmable materials and the nature of the DNA bond.Science,2015,347:840-851
31 Woo S,Rothemund P W.Programmable molecular recognition based on the geometry of DNA nanostructures.Nat Chem,2011,3:620-627
32 Millstone J E,Georganopoulou D G,Xu X,et al.DNA-Gold triangular nanoprism conjugates.Small,2010,4:2176-2180
33 Ouyang X,Li J,Liu H,et al.Rolling circle amplification-based DNA origami nanostructrures for intracellular delivery of immunostimulatory drugs.Small,2014,9:3082-3087
34 Tian C,Li X,Liu Z,et al.Directed self-assembly of DNA tiles into complex nanocages.Angew Chem Int Ed,2014,53:8041-8044
35 Han D,Pal S,Yang Y,et al.DNA gridiron nanostructures based on four-arm junctions.Science,2013,339:1412-1415
36 Zhang F,Jiang S,Wu S,et al.Complex wireframe DNA origami nanostructures with multi-arm junction vertices.Nat Nanotechnol,2015,10:779-784
37 And F A A,Sleiman H F.Modular access to structurally switchable 3D discrete DNA assemblies.J Am Chem Soc,2007,129:13376-13377
38 Zhang C,Macfarlane R J,Young K L,et al.A general approach to DNA-programmable atom equivalents.Nat Mater,2013,12:741-746
39 Benson E,Mohammed A,Gardell J,et al.DNA rendering of polyhedral meshes at the nanoscale.Nature,2015,523:441-444
40 Ke Y,Ong L L,Shih W M,et al.Three-Dimensional structures self-assembled from DNA bricks.Science,2012,338:1177-1183
41 He Y,Ye T,Su M,et al.Hierarchical self-assembly of DNA into symmetric supramolecular polyhedra.Nature,2008,452:198-201
42 Lee D S,Qian H,Tay C Y,et al.Cellular processing and destinies of artificial DNA nanostructures.Chem Soc Rev,2016,45:4199-4225
43 Petros R A,Desimone J M.Strategies in the design of nanoparticles for therapeutic applications.Nat Rev Drug Discovery,2010,9:615-627
44 Choi H S,Liu W,Liu F,et al.Design considerations for tumour-targeted nanoparticles.Nat Nanotechnol,2010,5:42-47
45 Davis M E,Chen Z G,Shin D M.Nanoparticle therapeutics:An emerging treatment modality for cancer.Nat Rev Drug Discovery,2008,7:771-782
46 Chou L Y T,Zagorovsky K,Chan W C W.DNA assembly of nanoparticle superstructures for controlled biological delivery and elimination.Nat Nanotechnol,2014,9:148-155
47 Keefe A D,Pai S,Ellington A.Aptamers as therapeutics.Nat Rev Drug Discovery,2010,9:537-550
48 Kozlov M M,Mcmahon H T,Chernomordik L V.Protein-driven membrane stresses in fusion and fission.Trends Biochem Sci,2010,35:699-706
49 Hu Q,Li H,Wang L,et al.DNA nanotechnology-enabled drug delivery systems.Chem Rev,2018,doi:10.1021/acs.chemrev.7b00663
50 Hu Q,Wang S,Wang L,et al.DNA nanostructure-based systems for intelligent delivery of therapeutic oligonucleotides.Adv Healthcare Mater,2018,7:1701153
51 Bujold K E,Lacroix A,Sleiman H F.DNA nanostructures at the interface with biology.Chem,2018,4:495-521
52 Wang P,Meyer T A,Pan V,et al.The beauty and utility of DNA origami.Chem,2017,2:359-382
53 Pinheiro A V,Han D,Shih W M,et al.Challenges and opportunities for structural DNA nanotechnology.Nat Nanotechnol,2011,6:763-772
54 Juliano R L.The delivery of therapeutic oligonucleotides.Nucleic Acids Res,2016,44:6518-6548
55 Panyam J,Labhasetwar V.Biodegradable nanoparticles for drug and gene delivery to cells and tissue.Adv Drug Delivery Rev,2012,64:61-71
56 Jensen S A,Day E S,Ko C H,et al.Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma.Sci Transl Med,2013,5:1-12
57 Chao J,Liu H,Su S,et al.Structural DNA nanotechnology for intelligent drug delivery.Small,2015,10:4626-4635
58 Peer D,Karp J M,Hong S,et al.Nanocarriers as an emerging platform for cancer therapy.Nat Nanotechnol,2007,2:751-760
59 Afonin K A,Viard M,Martins A N,et al.Activation of different split functionalities on re-association of RNA-DNA hybrids.Nat Nanotechnol,2013,8:296-304
60 Lee J B,Hong J,Bonner D K,et al.Self-assembled RNA interference microsponges for efficient siRNA delivery.Nat Mater,2012,11:316-322
61 Choi C H,Hao L,Narayan S P,et al.Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates.Proc Natl Acad Sci USA,2013,110:7625-7630
62 Liang L,Li J,Li Q,et al.Single-particle tracking and modulation of cell entry pathways of a tetrahedral DNA nanostructure in live cells.Angew Chem Int Ed,2014,53:7745-7750
63 Lee H,Lyttonjean A K R,Chen Y,et al.Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery.Nat Nanotechnol,2013,7:389-393
64 Bujold K E,Hsu J C,Sleiman H F.Optimized DNA“Nanosuitcases”for encapsulation and conditional release of siRNA.J Am Chem Soc,2016,138:14030-14038
65 Lacroix A,Edwardson T G W,Hancock M A,et al.Development of DNA nanostructures for high affinity binding to human serum albumin.J Am Chem Soc,2017,139:7355-7362
66 Rahman M A,Wang P,Zhao Z,et al.Systemic delivery of Bc12-targeting siRNA by DNA nanoparticles suppresses cancer cell growth.Angew Chem Int Ed,2017,56:16023-16027
67 Hong C A,Jang B,Jeong E H,et al.Self-assembled DNA nanostructures prepared by rolling circle amplification for the delivery of siRNA conjugates.Chem Commun,2014,50:13049-13051
68 Chen G,Liu D,He C,et al.Enzymatic synthesis of periodic DNA nanoribbons for intracellular pH sensing and gene silencing.J Am Chem Soc,2015,137:3844-3851
69 Ren K,Liu Y,Wu J,et al.A DNA dual lock-and-key strategy for cell-subtype-specific siRNA delivery.Nat Commun,2016,7:13580
70 Ruan W,Zheng M,An Y,et al.DNA nanoclew templated spherical nucleic acids for siRNA delivery.Chem Commun,2018,54:3609-3612
71 Nuhn L,Hirsch M,Krieg B,et al.Cationic nanohydrogel particles as potential siRNA carriers for cellular delivery.ACS Nano,2012,6:2198-2214
72 Dahlman J E,Barnes C,Khan O F,et al.In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight.Nat Nanotechnol,2014,9:648-655
73 Li J,Zheng C,Cansiz S,et al.Self-assembly of DNA nanohydrogels with controllable size and stimuli-responsive property for targeted gene regulation therapy.J Am Chem Soc,2015,137:1412-1415
74 Ding F,Mou Q,Ma Y,et al.Crosslinked nucleic acid nanogel for effective siRNA delivery and antitumor therapy.Angew Chem Int Ed,2018,57:3064-3068
75 You Z,Qian H,Wang C,et al.Regulation of vascular smooth muscle cell autophagy by DNA nanotube-conjugated mTOR siRNA.Biomaterials,2015,67:137-150
76 Wang Y,You Z,Du J,et al.Self-assembled triangular DNA nanoparticles are an efficient system for gene delivery.J Control Release,2016,233:126-135
77 Ryou S M,Kim S,Jang H H,et al.Delivery of shRNA using gold nanoparticle-DNA oligonucleotide conjugates as a universal carrier.Biochem Biophys Res Commun,2010,398:542-546
78 Luo M,Wang H,Wang Z,et al.A STING-activating nanovaccine for cancer immunotherapy.Nat Nanotechnol,2017,12:648-654