ДНК-нанотехнологии 1 введение и основные методы / sun2014

Drug Delivery

With the rapid development of nanotechnology, some nanomaterials have already been explored as drug delivery carriers for the purpose of improving the delivery of non-water-soluble drugs, of targeting specific cell or

Figure 11. Single nucleotide polymorphisms experiment. When target for each corresponding letter probes was added, that letter pattern vanished. Reprinted with permission from [175], H. K. K. Subramanian, et al., The label-free unambiguous detection and symbolic display of single nucleotide polymorphisms on DNA origami. Nano Lett. 11, 910 (2011). © 2011, American Chemical Society.

J. Biomed. Nanotechnol. 10, 2350–2370, 2014

DNA Nanotechnology and Its Applications in Biomedical Research	Sun et al.

Figure 10. Schematic showing of the 4 × 4-tile-formed DNA 2D barcode array and its detection mechanism. (a) shows the tile design, different-colored array formation, and color changes after binding with target molecules; (b) the mechanism of the interaction between the probe and target molecules. Reprinted with permission from [170], C. Lin, et al., Self-assembled combinatorial encoding nanoarrays for multiplexed biosensing. Nano Lett. 7, 507 (2007). © 2007, American Chemical Society.

technique, makes DNA nanostructures ideal for label-free	with electrochemical techniques, they were able to detect a
nucleic acids detections, which can avoid the tedious pro-	variety of interested targeted molecules.177–180 Research on
cess of the multi-coded fluorescence DNA array system.	patterning DNA nanostructures on gold surfaces with the
An origami chip for label-free RNA detection173 was	help of lithography also made great progress.181–184 The
first reported by Yan’ group; a rectangular DNA origami	combination of top-down and bottom-up technology will
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tile was used as the chip, multiple single-stranded DNA	greatly help DNA nanostructures’ application in biosens-
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probes targeting specific RNA sequences were precisely	ing field.

Copyright: American Scientific Publishers patterned on the origami scaffold; upon binding of the tar-

geted RNA molecules on DNA probes, a designed double helical DNA-RNA-V-Shaped junctions formed, created designed features visualized by AFM. Index spots were created on each origami tile so that the detection tiles could be differentiated, allowing for simultaneously, multi-target detection. Later, an asymmetric map-like DNA origami tile was used to replace the rectangular tile, which eliminated the symmetry feature, avoids the use of index spots.174

A different approach was used to detect single nucleotide polymorphisms on DNA origami.175 Four visible letters features corresponding to A, T, G, C were created first on the origami, with each letter contains distinct sequences; when target DNA strand with the right nucleotide variation was added onto the surface of the origami, the letter strand was replaced and the corresponding letter pattern disappeared. Most recently, DNA origami single-molecule-beacons were prepared also for label-free detection. By adding different control features, the devices were able to detect a range of targets, including miRNA and proteins,176 by AFM imaging. A DNA tetrahedral structure was used by Fan’s group to improve the conventional DNA-on-gold surface microarray detection. By attaching the DNA probes on the vertex of the DNA tetrahedron, which deposited onto the gold surface through thio groups modified on three of its vertexes, the accessibility of the probes vastly improved. Combining

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J. Biomed. Nanotechnol. 10, 2350–2370, 2014

	Sun et al.		DNA Nanotechnology and Its Applications in Biomedical Research
	tissues, of improving cell-uptake of small drugs, of real-		cytotoxicity test showed no significant cell death was
	time monitoring the delivery process, among others. Some		observed, which proved DNA nanotubes are biocompati-
	drug delivery nanosystems, including liposome and poly-		ble as expected. But the relative large size of the DNA
	mer nanoparticles, have already had some success and		nanotubes they used, 10–40 m, might make the nano-
	been approved for clinical use, but still haven’t had signif-		tubes difficult to maintain their designed structure during
	icant impact yet.185 Developing biocompatible, multifunc-		the cell uptaking process.
	tional drug delivery nanosystems remains the key for the		Sleiman’s group later reported their DNA nanotubes
	application of nanotechnology on drug delivery. It is desir-		with controlled length, assembled with rolling-circle-
	able to develop multifunctional drug nanocarriers, which		amplification (RCA), had good cell-uptaking efficacy, and
	have cage-like structures that can encapsulate one or multi-		they also demonstrate the integrity of their DNA nano-
	ple drugs inside the cage, so the drugs will only be released		tubes inside the human cervical cancer (HeLa) cells.104
	when the nanocarriers get to the targeted sites and receive		The more compact DNA tetrahedron nanostructure devel-
	specific signals; the drug nanocarriers also should have		oped by Turberfield’s group50 51 was later explored as
	modification sites for targeting ligands to deliver drugs to		another potential drug delivery carrier. The DNA tetra-
	interested cell or tissues; the drug nanocarriers also should		hedron structure was first tested for its resistance against
	contain imaging reagents (or they are luminescent them-		enzymatic digestions,187 and the results showed that the
	selves) allowing real-time monitoring the drug delivery		DNA tetrahedron structure has superior stability over DNA
	processes and their efficacy.		single strands against enzymatic digestions. In 10% fetal
	DNA 3D nanostructures have all the features to be		bovine serum (consisting complex mixture of nucleases
	promising candidates for multifunction drug delivery:		and other proteins), the DNA tetrahedron structure can
	they are biocompatible; can be easily modified at multi-		be stable for 42 hours, comparing to only 0.8 hours for
	ple addressable positions; some well-developed cage-like		DNA single strands. This indicates that the DNA tetra-
	DNA 3D structures have the	cavities to accommo-	hedron structure can exist inside cells with integrity for
	date drug cargos; and 3D DNA nanostructures can be		a certain period of time, and could be used as drug
	reconfigurable with special designs and control methods.		delivery carrier. Later, the transfection efficacy of this
	In recent years, some excellent researches have already		DNA tetrahedron nanostructure into plated human embry-
	been done to explore the application of DNA nano-		onic kidney cells was tested. Fluorescence dyes, Cy5
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	structures as multifunctional drug delivery nanosystems.		and Cy3 were attached to the DNA tetrahedron at spe-
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	A dual-functionalized DNA nanotube structure was first		cific positions, fluorescence study results clearly showed
		Copyright: American Scientific Publishers
	used to deliver covalently linked fluorescence dye Cy3		the DNA tetrahedron can easily transfect into the cells,
	into the nasopharyngeal epidermal carcinoma KB cells by		and the DNA tetrahedron structure remain intact in cells
	Mao’s group;186 folate molecules were conjugated onto		even 48 hours after transfection.188 Then, Fan’s group
	the DNA nanotube as targeting ligands for targeting folate		attached unmethylated cytosine-phosphate-guanine (CpG)
	receptors (FRs) over-expressed on the surface of the KB		motifs to the DNA tetrahedron structure for immunostim-
	cells (see Fig. 12). Comparing to single-stranded DNAs,		ulatory study (see Fig. 13),189 once getting into the cells,
	fluorescence images clearly showed that some of the		the therapeutic CpG oligodeoxynucleotides will bind and
	DNA nanotubes transfect into the targeted cells, and the		allosterically activates Toll-like receptor 9 (TLR9), which
			then activates downstream pathways to induce immunos-
			timulatory effects, producing high-level secretion of vari-
			ous pro-inflammatory cytokines including tumor necrosis
			factor (TNF)-R, interleukin (IL)-6, and IL-12. They found
			that the DNA tetrahedron structures could noninvasively
			and efficiently enter macrophage-like RAW264.7 cells
			without the aid of transfection agents. And their ELISA
			assays results showed that functional CpG-DNA tetrahe-
			dron nanostructures dramatically induced the production of
			various proinflammatory cytokines including tumor necro-
			sis factor (TNF)-R, interleukin (IL)-6, and IL-12. The level
			of immunostimulatory effects of CpG attached on DNA
			tetrahedron nanostructures increased by 9 to 18 times com-
	Figure 12. Schematic showing of	the construction of the	paring to free CpG oligodeoxynucleotides.
	dual-functionalized DNA nanotube and its delivery process.		Langer and Anderson’s group later tested the therapeu-
	(a) The design of the DNA nanotube; (b) cell targeting and		tic potential of DNA tetrahedron nanostructures as siRNA
	delivery mechanism. Reprinted with permission from [186],
			nanocarrier in vivo.190 They used DNA tetrahedron nano-
	S. H. Ko, et al., DNA nanotubes as combinatorial vehicles for
			structures as nanocarriers, attached anti-luciferase siRNA
	cellular delivery. Biomacromolecules 9, 3039 (2008). © 2008,
	American Chemical Society.		onto specific sites of the DNA tetrahedral, also with

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DNA Nanotechnology and Its Applications in Biomedical Research

Figure 13. Schematic showing of the assembly of CpG bearing DNA tetrahedron and its immunostimulatory effect. Reprinted with permission from [189], J. Li, et al., Selfassembled multivalent DNA nanostructures for noninvasive intracellular delivery of immunostimulatory CpG oligonucleotides. ACS Nano 5, 8783 (2011). © 2011, American Chemical Society.

	conjugated folate (FA) targeting folate receptor overex-				Figure 14.	Schematic showing of DNA tetrahedral nano-
					structures as scaffold for the assembly of adjuvant-antigen
	pressing KB cells. Either by tail-vein injection or intratu-
					vaccine complex. The CpG adjuvant molecules shown in pur-
	mor injection, folate (FA)-conjugated DNA tetrahedra with				ple hangers at the outside of the tetrahedral; the streptavidin
	anti-luciferase siRNA were delivered into mice. By silenc-				antigen shown in red. The vaccine complexes were injected
	ing gene of firefly luciferase expressing KB xenografts,				into mice, and bound specifically to B cells and nonspecifi-
					cally to dendritic cells and macrophages. The complexes are
	one should expect a decrease of bioluminescent intensity
					internalized by the three types of antigen-presenting cells,
	in the tumor, their results clearly showed that a decrease
					disassembled, and the individual peptide antigens are subse-
	of 60% in bioluminescent intensity for both tail-vein and				quently presented to T cells to activate B cell response and
	intratumor injections, which means that DNA tetrahedron				antibody production. Reprinted with permission from [191],
	nanostructures have a promising future as nanocarriers for				X. Liu, et	al., A DNA nanostructure platform for directed
					assembly of synthetic vaccines. Nano Lett. 12, 4254 (2012).
	siRNA and possible other drugs molecules.
					© 2012, American Chemical Society.
	Yan’s group later used DNA tetrahedral nanostructures
	as platform for the assembly of synthetic			vaccine, and
			191
	tested the immune	Delivered by Publishing Technologyshow anto:efficientRice Universityand specific internalization for killing
		response in vivo.		They utilized
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	the addressability of the DNA tetrahedral nanostructures,				epithelial cancer cells.
		Copyright: American Scientific Publishers
	attached a model antigen, streptavidin (STV), and a rep-				Krishnan’s group used their DNA icosahedral nano-
	resentative adjuvant, CpG oligodeoxynucleotides onto the				structures made from DNA five-way junction motif as
	designed sites, and assembled a synthetic vaccine complex				nanocarrier cages, encapsulated Fluorescein isothiocyanate
	(see Fig. 14), once the vaccine complex were injected into				(FITC)-Dextran (FD) as cargos inside the cages.194 Their
	mice, they bound specifically to B cells and nonspecif-				results showed that the host–cargo complex was uptaken
	ically to dendritic cells and macrophages, and activated				only by specific cells (coelomocytes) in Caenorhabditis
	T cells and triggered antibody production. This synthetic				elegans that expressed the anionic ligand-binding receptor
	vaccine complex has similar size and shape as a natural				(ALBR). Later, by redesigning their icosahedral structures,
	viral particle. Their results showed that, comparing to free				they divided their icosahedra into two half parts, which
	CpG plus free STV, fully-assembled tetrahedral-STV-CpG				added a cyclic-di-GMP (cdGMP) binding aptamer struc-
	synthetic vaccine complex generated a much higher level				ture into the middle connection part which associating the
	of anti-STV IgG antibodies in vivo. And no antibody was				two half parts together. Then their DNA icosahedral struc-
	detected against the DNA tetrahedral structures alone. This				tures become drug delivery nanosystems capable releas-
	experiment shows that DNA tetrahedral structures not only				ing drug cargos in a controlled manner, in response to an
	can serve as a nanocarrier system for drug, but also can				external trigger, namely cyclic-di-GMP (cdGMP).195
	be used to assemble vaccine like structures for biomedical				All the polyhedral DNA nanostructures mentioned
	purpose.				above showed great promise as efficient drug delivery
	Polypod-like DNA structures were also developed for				nanocarriers, even in a controlled-release function. But
	efficient delivery of immunostimulatory CpG to immune				one of the concerns regarding the polyhedral DNA nano-
	cells.192 Their results showed that increasing pod num-				structures is that they all have porous surfaces, which
	ber is directly linked with efficient cellular uptake, and				could limit their application as totally-closed cage-like
	large amount of cytokine production from TLR9-positive				drug delivery nanosystems. DNA origami 3D nano-
	cells. A distinct five-point-star motif and aptamer-				structures have their structural advantages as topological-
	conjugated six-point-star motif were developed to inter-				closed drug delivery nanocarriers. Some wonderful works
	molecularly construct DNA icosahedra as a nanocarrier				have already done to explore DNA origami structures as
	for doxorubicin.193	Aptamer-conjugated doxorubicin-			potential drug delivery nanocarriers. First, Yan’s group
	intercalated DNA icosahedra (Doxo@Apt-DNA-icosa)				tested the	stabilities of different shaped DNA origami
	2362					J. Biomed. Nanotechnol. 10, 2350–2370, 2014

Sun et al.			DNA Nanotechnology and Its Applications in Biomedical Research
nanostructures in lysates from various normal and can-			visualization of the intracellular location and stability of
cerous cell lines. After incubating DNA origami nano-			DNA origami;203 this technique will bring more alterna-
structures with cell lysates for up to 12 hours, they			tives to monitor the drug delivery process of DNA nano-
found the DNA origami structures were still intact.196 And			structures, especially in some environment, where small
the functional DNA origami structures could be sepa-			organic dye molecules might be difficult to stay intact.
rated from the cell lysates and maintaining their structural			Because their biocompatibility, and promising features
integrity and functionality.197			as multifunctional drug nanocarriers, DNA nanostructures
Liedl’s group then used a DNA	origami	nanotubu-	could become import nanosystems for smart, controlled
lar structure as delivery nanocarrier	for the	therapeu-	drug delivery applications. The stability concern about the
tic CpG oligodeoxynucleotides.198 Their results showed			DNA nanostructures might be solved by using stable DNA
that the DNA origami nanotube also can enter the cell			analog-DNA heterostructures,204 or by chemical modifica-
effectively and activate Toll-like receptor 9 (TLR9) and			tion DNA nanostructures at designed positions.
then the downstream pathway. A twisted DNA origami
nanostructure was also used for optimal delivery of the			Biomimetic Assemblies
anthracycline doxorubicin (Dox) to human breast cancer			One best way to understand the function of the living cells
cells.199 Another triangular DNA origami structure also			and cell networks, is to assemble synthetic cells or cell net-
was used for the delivery of doxorubicin anticancer drug			works, which can mimic all the functions of the living cells
to human breast cancer cell.200 In both cases, doxorubicin			and cell networks. Because of its excellent self-assembly
was attached to the DNA origami structure by intercalating			properties, DNA is a promising material for synthetic biol-
between the DNA bases.			ogy applications. Some works have already proven that
But the DNA origami nanotube198 used for the delivery			DNA nanostructures can be used for biomimetic appli-
of CpG oligodeoxynucleotides, and the two DNA origami			cations. Luo’ group created a cell-free protein-producing
structures199 200 used for doxorubicin drug delivery men-			DNA hydrogel system.205 By joining genomic DNA frag-
tioned above, all don’t have the controlled-drug-release			ments together with a DNA four-way-junction motif
function. Recently, A DNA origami nanorobot,201 with a			(called X-DNA) using ligase, they assembled a gene-
hexagonal barrel shaped cage-like structure was developed			containing DNA hydrogel system inside polydimethyl-
for controlled delivery of cargos. Two domains of the			siloxane (PDMS) moulds, thus prepared DNA hydrogel
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DNA origami barrel structure are covalently attached in			pads with well-defined dimensions with controlled poros-
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the rear by single-stranded scaffold hinges; two specific			ity. When immersed in cell extracts containing compo-
Copyright: American Scientific Publishers
DNA aptamer–based locks are created to close the barrel			nents, such as RNA polymerase and ribosome, the DNA
in the front. Once a correct combination of two protein			hydrogel pads can serve as gene template for in vitro cell
antigen are met, the aptamers will undergo target-induced			free protein synthesis. They tested a total of 16 different
switching between an aptamer-complement duplex and			protein-producing DNA hydrogels containing 16 different
an aptamer-target complex, in turn, open the barrel, and			genes, and successfully produced all 16 proteins includ-
release the inside payloads. In their experiment, different			ing membrane and toxic proteins. Their results proved
aptamer-based locks were used for testing the open and			that their DNA hydrogel system can serve as a general
close function of their DNA origami nanorobot; and differ-			protein production technology. Their work represented an
ent antibody payloads were added into the nanorobot cage			important milestone for the use of DNA nanostructures
to investigate their nanorobot application on interfering			on engineering higher functional complexity in synthetic
with cell signaling pathways. Their results clearly showed			biological systems.206
their DNA origami nanorobot can release drug payloads in			Also it is important for biomedical research to gain clear
a controlled manner, and can carry multiple drug payloads			information about individual cells, and cell-cell interac-
at the same time. This is big step towards developing a			tions. Krishnan’s group developed a DNA nanomachine
multifunctional controlled drug delivery nanosystem.			system based on I-motif DNA. This DNA nanomachine,
One concern about DNA origami structure as drug			called the I-switch, consists of two DNA duplexes con-
delivery nanocarrier is that it requires too many short			nected to each other by a flexible hinge and bearing cyto-
DNA staple strands to build; some of the staple strands			sine rich single-stranded overhangs at the duplex termini.
might possess biological effects to the cell by themselves.			At acidic and neutral pH conditions, the I-switch DNA
A Rolling-Circle-Amplification (RCA)-based approach to			nanomachine will adapt “closed” and “open” conforma-
fold well-defined DNA origami nanostructures with only			tions respectively. By attaching a pair of fluorescent dyes
several staple strands was developed recently, and was			at designed positions of this I-switch DNA nanomachine,
used as efficient delivery carriers for CpG immunos-			it forms the molecular basis of a fluorescence resonance
timulatory drugs;202 this approach might pave the way			energy transfer (FRET)-based pH sensor. They used this
to simplify the structure design of other DNA origami			DNA nanomachine successfully mapped spatiotemporal
nanocarriers to eliminate possible interfering DNA strands.			pH changes associated with endosome maturation inside
Also a label-free fluorescent probe	was developed for		living cells in culture;207 and later in multicellular living
J. Biomed. Nanotechnol. 10, 2350–2370, 2014			2363

SUMMARY

DNA nanotechnology has seen its rapid growth in the past two decades. The development of precisely controlled nanoscale assemblies of 2D and 3D DNA nanostructures, combined with other technology developed from chemistry, material science, physical science, and biotechnology, has made DNA nanotechnology a promising means to be applied in better understanding biological phenomenon

J. Biomed. Nanotechnol. 10, 2350–2370, 2014

DNA Nanotechnology and Its Applications in Biomedical Research

Sun et al.

organisms, Caenorhabditis elegans;208 and most recently,

the DNA origami structures at the gate of glass nanocap-

they used two distinct DNA nanomachines within the

illaries. By tuning the pore size they were able to control

same living cell to simultaneously map pH gradients along

the folding of dsDNA passing through the nanopore; and

two different but intersecting cellular entry pathways,209

by specific introduction of binding sites (a short ssDNA

the furin retrograde endocytic pathway and the transfer-

with designed sequence) in the DNA origami nanopore,

rin endocytic/recycling pathway. This approach represents

they were able to selectively detect ssDNA molecules.217

a first successful application of DNA nanotechnology on

And recently, a breakthrough was made by Dietz and

cell analysis. Liu’s group used Y-DNA motif and linkers to

Simmel’s group. Inspired by the structure of the bac-

form DNA hydrogel, served as a cover to a polydimethyl-

terial protein pore a-hemolysin, they constructed a syn-

siloxane (PDMS) chip with circular microwells at different

thetic lipid membrane channel218 made entirely from DNA

diameters are designed and prepared by soft lithography,

origami nanostructure, with cholesterol modification at

cells are trapped inside those microwells separately, one

designed positions. The barrel-like structure contains a

cell in one well.210 Since the DNA hydrogel is permeable,

stem that penetrated and spanned a lipid membrane, and

nutrients for the cell can pass through the hydrogel cover.

a cap adhered to the membrane via 26 cholesterol moi-

Also the DNA hydrogel can be specifically digested by

ety. The stem protrudes centrally from the barrel and

restriction enzymes, which open the hydrogel cover for a

consists of six double-helical DNA domains that form a

specific cell and release it. This design allows successful

hollow tube which acts as a transmembrane channel, with

single cell level analysis, and can avoid the misinterpreta-

a diameter of 2 nm and a length of 42 nm. Single-

tion for specific cell properties by bulk cell analysis.

channel electrophysiological experiments showed that the

Meanwhile, understanding the cell–cell interactions is

channel conducted an electrical current proportional to

essential to understand the function of multicellular organ-

the potential that is placed across the membrane, and

isms. Yan’s group utilized DNA 4 × 4 tiles as scaffold,

demonstrated stochastic gating-fluctuations between open

attached cell-targeting aptamers as directing reagents, suc-

and closed conformations resemble those seen in natural

cessfully aligned two types of cell into close vicinity, and

biological transmembrane protein channels. The synthetic

analyzed cell–cell interactions.211 This might be a first step

origami channel could also be used for molecular detec-

towards building multicellular organism; also might has

tion applications, as their results showed that their channel

significance in disease treatment, for example, it might fos-

was able to monitor the zipping-unzipping of DNA hair-

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ter the T–B cell interactions required to generate an effec-

pin structures and folding-unfolding of DNA G-quadruplex

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tive immune response. The development of methods for

structures. This synthetic DNA origami lipid membrane

Copyright: American Scientific Publishers

the modification of cell surfaces with single-stranded DNA

channel has the potential to make great impact on biomed-

oligomers212 provided the means to use different designs

ical research, such as manipulation of the cells and drug

DNA nanoscaffold for the alignment of various interested

delivery.219 220

cells.

Later,

Howorka’s

group used

chemical modification

In nature, a lot of protein and peptide channels inserted

methods

to

prepare

DNA

origami

nanopores

which

into the

lipid bilayer membranes

of living cells act as

have better interaction with lipid membranes. First, they

transporting pathway water, ions and others for the cells’

used ethyl-modified

phosphorothioate

groups to

form a

normal

growth. Many

synthetic

nanopores mimic

the

hydrophobic belt around the DNA origami nanopores to

protein

channel were

created for

the biodetecting

and

minimize the negative charges and mimic natural pro-

biosensing purpose. DNA nanostructures have also been

tein pores.221

And

then

they

used only

two porphyrin-

explored for the application as nanopore materials,

but

based hydrophobic

tags

attached

on

the

DNA

origami

mostly as gating purpose. First, Liu’s group G-quadruplex

nanopore

to

successfully anchor

the

highly negatively

DNA was immobilized onto a

synthetic nanopore,213

charged DNA nanostructure into the hydrophobic core of

which undergoes a potassium-responsive conformational

lipid bilayers.222 Their works greatly improved the stabil-

change at a certain potassium concentration range, as a

ity of the synthetic DNA origami lipid membrane channel,

result, changed the pore size of their synthetic nanopore.

enhanced the possibility of its application in biomedical

Then Dietz’s group utilized the

permeability of DNA

research.

origami,214 applied a DNA origami nanoplate as gatekeepers for solid-state nanopores, and successfully gained control over both the geometrical and chemical specifications of solid-state nanopores.215 Keyser’s group explored different approaches. In one experiment, they inserted a DNA origami nanopore-like structure inside a solid-state nanopore,216 and employed their hybrid nanopore system for the successful detection of -DNA molecules. In another experiment, they used a DNA origami nanoplate structure with a pore opening in the middle, and attached

2364

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Sun et al.

DNA Nanotechnology and Its Applications in Biomedical Research

and solving biomedical problems, especially in disease

20.

D. Han, S. Pal, Y. Yang, S. Jiang, J. Nangeave, Y. Liu, and H. Yan,

early diagnosis and targeted treatment. And we can foresee

DNA gridiron nanostructures based on four-arm junctions. Science

that DNA nanotechnology will make even greater impacts

339, 1412 (2013).

21.

D. Liu, M. Wang, Z. Deng, R. Walulu, and C. Mao, Tensegrity:

on biomedical research in the near future.

Construction of rigid DNA triangles with flexible four-arm DNA

Acknowledgments: We are grateful to Dr. Nadrian

junctions. J. Am. Chem. Soc. 126, 2324 (2004).

22.

and T. H. LaBean,

H. Yan, S. H. Park, G. Ginkelstein, J. H. Reif,

C. Seeman for the courtesy images used in Figures 1 and 2.

DNA templated self-assembly of protein arrays and highly conduc-

We also thank the financial supports from National Sci-

23.

tive nanowires. Science 301, 1882 (2003)

E. Ribbe, and C. Mao,

ence Foundation China (21373151) and Tianjin Medical

Y. He, Y. Tian, Y. Chen, Z. Deng, A.

University (TMU start-up fund).

Sequence symmetry as a tool for designing DNA nanostructures.

Angew. Chem., Int. Ed. 44, 6694 (2005)

24.

K. Lund, Y. Liu, S. Lindsay, and

H. Yan,

Self-assembling a molec-

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