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b822719e 2625..2636

DNA nanomachines and their functional evolution

Huajie Liuw and Dongsheng Liu*

Received (in Cambridge. UK) 17th December 2008, Accepted 10th March 2009

First published as an Advance Article on the web 9th April 2009

DOI: 10.1039/b822719e

Since the establishment of the Watson–Crick model more than five decades ago, the

understandings of DNA structures are well sufficient to enable applications of DNA in designing

and assembling two-dimensional (2D) and three-dimensional (3D) structures at the nanoscale.

Furthermore, the conformational switchability of DNA also enables the fabrication of nanoscale

molecular machines, which can perform movements upon stimuli. In this article, we will

summarize the present efforts on constructions of DNA nanomachines based on different driven

mechanisms, and further discuss their evolutional processes, in order to find applications and

future development directions.

Introduction

DNA has been seen to play an extraordinary important role in

life science more than five decades since the establishment

of the Watson–Crick model. Tracing back to its chemical

essence, DNA has also received attention in material sciences,

especially in nanoscience.1 Based on specific base-pair

formation and programmable sequence, DNA nanostructure

assembly, pioneered by Seeman et al.2–6 in the 1980s, has now

reached the stage of facile fabrication of complicated 2D7–12

and even 3D nanostructures via designed hybridization

processes.13–16 However, compared to these static nano-

structures, a more challenging aspect in this field is fabricating

nanomachines which can perform nanoscale movements in

response to external stimuli.17–20 Although protein is the

material chosen by Nature to facilitate nanomachines in

living beings,21,22 the clearer structures, established synthesis

and modification methods and clearer driven mechanisms

of DNA nanomachines, have been demonstrated to be of

interest for material research as well as theoretical studies.

From the first effort to control DNA motion,23 the last

decade has witnessed an explosion of interest and effort in

this field.24–29

In this review, we have sorted out several basic DNA

nanomachine types by driven mechanism. The consequent

evolution on the power input method to improve the kinetics

of each type is summarized to give a perspective on

their development trends. We then highlight the efforts on

measuring the mechanical outputs of DNA nanomachines as

well as employing these outputs to achieve new functional

devices and materials. Through these analyses, we will try to

provide some perspectives on the development of DNA

nanomachines in the near future.

National Centre for NanoScience & Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, 100190, China. E-mail: liuds@nanoctr.cn; Fax: +86-10-62656765; Tel: +86-10-82545589

Huajie Liu

Dr Huajie Liu received his BS in applied chemistry and MS in inorganic chemistry at Tongji University. From 2005 to 2008, he was a PhD student under the supervision of Prof. Dongsheng Liu at the National Center for Nano- science and Technology. During his PhD period, he worked on developing new control-modes and applications of DNA nanomotors. He is currently working as a postdoctoral fellow with Prof. Kurt V. Gothelf at the University of

Aarhus, where his research concentrates on DNA directed assembly of nanomaterials.

Dongsheng Liu

Professor Dongsheng Liu graduated from the University of Science and Technology of China with a BS degree in 1993. After working in the Institute of Chemistry, Chinese Academy of Sciences for six years, he went to the Hong Kong Polytechnic Uni- versity and finished his PhD there under the supervision of Professor A. S. C. Chan in 2002. He moved to the UK afterwards and worked as a postdoc research associate in NanoIRC and Department of

Chemistry, Cambridge University. In 2005, he took the position as a principal investigator in the National Centre for Nano- Science and Technology, China. His researches are mainly focused on using biomolecules to fabricate nanostructures and nanodevices.

w Current address: Centre for DNA Nanotechnology at Department of Chemistry and iNANO, University of Aarhus, Denmark.

This journal is c The Royal Society of Chemistry 2009 Chem. Commun., 2009, 2625–2636 | 2625

FEATURE ARTICLE www.rsc.org/chemcomm | ChemComm

Prototype DNA nanomachines

A machine could be defined as any device that uses energy to

perform some activity, e.g.mechanical movement. We also use

word ‘‘motor’’ to describe a device that converts various forms

of energy into kinetic energy for mechanical work. As outlined

in an editorial18 by Stoddart: ‘‘organization, the power source,

and work of a repetitive nature’’ are the most important

characteristics of a molecular machine. From this point of

view, the DNA nanomachine could be regarded as a kind of

molecular machine that is made up of assembled DNA

structures integrated with an external stimuli responding

mechanism. Thus all established DNA nanomachines

could be sorted into several catalogues by their original driven

mechanisms. In the following, we will summarize the

variation of each prototype to map their development trends,

respectively.

DNA nanomachines controlled by ‘‘fuel-strands’’

It is well known that a short DNA strand can be replaced by a

longer strand to form a more stable duplex, which is called

‘‘chain-exchange reaction’’ or ‘‘strand-exchange reaction’’.

This reaction has been employed to induce motions to

DNA-based nanostructures. In 2000, Yurke et al. reported

the first hybridization energy-driven DNA nanomachine

which resembles a pair of tweezers (Fig. 1).30 Their device is

assembled by three single-strands which can form two rigid

duplex arms connected by a hinge section and two dangling

ends linked to arms. At the ‘‘open’’ state, two ends of the arms

are thermodynamically separated. To ‘‘close’’ the tweezers, an

additional fourth strand F hybridizes with both dangling ends

and pulls the two arms together. The device could be reopened

by F’s fully complementary strand F0 because duplex FF0 has a

lower free energy (note an overhang section on F is the starting

point for FF0 hybridization). The alternating addition of F and

F0 will cycle the machine and produce duplex FF0 as waste.

Since the machine is powered by competitive hybridization,

the authors called the stimuli, DNA F and F0, as ‘‘fuel’’ and

‘‘anti-fuel’’. Overall, one switching is able to generate a force

of about 15 pN, with a maximum separation of the arm

ends of about 6 nm or 501; FRET and recently sp-FRET31

techniques have been used to monitor the motions. The

modifications of this design in following years have led to

some variants: an actuator32 and a three-state nanomachine33

that looks like a combination of tweezers and actuator.

This fuel-strands strategy has also been employed to drive

different DNA assemblies to move: Yan and Seeman proposed

a robust DNA nanomachine34 whose motions are between two

topological motifs: four-stranded PX and JX2 complexes. The

addition of DNA fuels will induce a four-step rotation.

A noticeable experimental detail is the use of biotinylated

fuel-strands to remove duplex wastes. By covalently linking

PX–JX2 machines linearly, the rotations of DNA machines

in these arrays could be controlled synchronously and be

visualized by atomic force microscopy (AFM). RNA has also

been exploited to control this device.35 Extension of this

two-state machine to a three-state one has recently been done

by the same group.36

In addition to duplexes, DNA can form unusual hybridized

structures such as triplexes and quadruplexes. It has been

proven by the groups of Tan37 and Mergny38 that the

quadruplex–duplex transition could generate mechanical

force. Their designs of G-quadruplex-based DNA nano-

machines are simpler than that of duplex-based models. In

their cases, only one G-rich strand is used to construct

the main body of the machine, that is, an intramolecular

G-quadruplex. The G-quadruplex state could be switched to

the duplex form by adding DNA fuel. Through this transition,

the distance between two ends of G-rich strand could be

controlled. Hence, we may regard the G-quadruplex and

duplex forms as closed and open states, respectively.

DNA nanomachines controlled by non-DNA stimuli

In principle, the above fuel-strands strategy could be applied

to all strand-exchange reaction-powered DNA nanomachines,

since, as we have mentioned, hybridization is the common

feature of DNA. However, the main disadvantage is these

reactions will result in cumulated duplex wastes. These useless

duplexes may compete with surrounding nanomachines. And

from the point of entropy flow, the accumulation of waste

DNA will increase the entropy of the system and will even-

tually destroy the machine.

To avoid duplex wastes, non-DNA stimuli should also be

choices for controlling motions. In fact, this approach has

already been proposed in the construction of the first

DNA-based nanomechanical device,23 in which case ethidium

ions are used as intercalators to induce branch point migration

in a tetramobile branched junction structure.

Simpler ions than ethidium have also been explored. Mao

and Seeman have demonstrated a DNA machine based on a

B–Z transition (Fig. 2).39 In the absence of Co(NH3)6 3+ ion,

sequence (CG)10 forms normal right-handed B-DNA. This

B-DNA can be transformed to left-handed Z-DNA upon the

addition of a high concentration of Co(NH3)6 3+ ion. The

Fig. 1 DNA tweezers controlled by ‘‘fuel’’ and ‘‘anti-fuel’’ strands.

Fuel strand F hybridizes with the dangling ends of the open state

machine (shown in blue and green) to pull the tweezers closed.

Hybridization with the overhang section of F (red) allows anti-fuel

strand F0 to remove F from the tweezers, forming a double-stranded

waste product FF0 and allowing the tweezers to open (reprinted with

permission from ref. 30; copyright 2000, Nature Publishing Group).

2626 | Chem. Commun., 2009, 2625–2636 This journal is c The Royal Society of Chemistry 2009

whole transition will generate a rotary motion with about

2 nm displacement in space.

Based on the G-quadruplex structure, Fahlman et al. have

constructed a nanopinching device which is sensitive to Sr2+

ion.40 This device’s working mechanism is due to sequenced

guanisines’ ability of forming G-quadruplexes in the presence

of metal ions. The addition of chelant EDTA to the solution

will enable the removal of Sr2+ ion from G-quadruplex

and break the pinched structure. Another ion-sensitive

G-quadruplex nanomachine was developed by Sugimoto’s

group.41 Their machine is assembled from modified DNA

strands, in which a coordination unit for divalent metal ions,

2,20-bipyridine, is used to link two GGGG fragments. In the

absence of M2+ ions, the modified sequence will self-assemble

into an antiparallel G-quadruplex. Adding Ni2+ ion to the

system will induce the rotation of the 2,20-bipyridine unit and

switch the structure to a parallel G-wire. Reverse reaction

could be started by EDTA. Strictly speaking, this machine

could not be regarded as an absolute DNA machine since its

driving force is derived from the ion-sensitivity of the

chemical unit.

For almost every chemical or biological system, the pH

value is a very important factor. For some DNA structures,

this is also true. For example, acidic pH favours the formation

of the four-stranded C-rich i-motif structure and C+GC triplet

because C base protonation (C+) will lead to extra hydrogen

bonds. This concept has first been applied to DNA nano-

machine construction by Liu and Balasubramanian.42 The

system comprises a 21mer strand X containing four CCC

stretches and its partial complementary strand Y (Fig. 3). At

slightly acidic pH, half protonated CCC stretches will form

intercalated C+C base pairs and induce X to fold into a

compact i-motif structure, corresponding to the machine’s

closed state. Raising pH to slightly basic value will unfold X

and form an extended duplex structure XY (open state).

Reversible switches between compact and extended states

can be produced by changing the pH and both processes are

completed in less than 5 s. In total, the operations of this

machine will result in a 5 nm linear movement and opening

and closing forces both larger than 10 pN; the wastes are only

salt and water from the neutralization reaction. The advan-

tages of this proton-driven nanomachine are obvious: it is

clear, quick, reliable and efficient. Similarly, the pH-sensitive

DNA triplex–duplex transitions have also been utilized to

build DNA nanomachines by the groups of Mao43 and

Zuccheri.44

Another approach to stimulate DNA structural transforma-

tion is changing the temperature. Although all nucleic acid

structures are sensitive to temperature change, Sugiyama’s

work demonstrated that DNA and RNA may have inverse

responses to thermal stimuli and therefore produce opposite

rotations.45 On the other hand, Isambert et al. concentrated on

controlling the folding kinetics of a DNA nanoswitch by

modulating its annealing cooling rate.46 By fast cooling, a

metastable conformation is favoured kinetically.

A protein-driven DNA nanomechanical device has been

proposed by Seeman’s group.47 In the report, E. coli integra-

tion host factor (IHF) has the ability to distort the device by

recognizing and binding specific DNA sequences in the device.

This device was suggested to be effective in measuring the

interaction between protein and DNA.

Unidirectional motions

The machines already described above have fixed links

between their primary elements. The motions of those DNA

machines are all fundamentally intramolecular. A challenge

arises as to mimic biological molecular motors21,22 such as

myosins, kinesins and dyneins that can perform unidirectional

motions on external tracks. One of the most attractive features

of this kind of motion is its ability to transport substances at

the nano- or micro-scale.

The simplest kind of unidirectional motion is linear walking.

This has now been achieved by DNA-based devices in a few

instances. In 2004, Seeman’s group reported a biped DNA

Fig. 2 An ion-triggered DNA rotary machine based on a B–Z

conformational transition. The motor consists of two DNA double

crossover (DX) molecules and at the centre of the connecting helix is a

20-nucleotide region of proto-Z DNA shown in yellow. Fluorescent

dyes fluorescein (green) and Cy3 (magenta) are attached to the free

hairpins near the middle of the molecule. When the transition occurs,

the two DX molecules change their relative positions and the separa-

tion of the dyes (reprinted with permission from ref. 39; copyright

1999, Nature Publishing Group).

Fig. 3 An i-motif DNA-based nanomotor driven by pH change.

Strand X contains four CCC stretches and can form a four-stranded

i-motif structure in slightly acidic environment. With the increase of

pH, the i-motif structure will be destroyed and X0s partial comple-

mentary strand Y will hybridize with X to form a duplex (reprinted

with permission from ref. 42; copyright 2003, Wiley Interscience).

This journal is c The Royal Society of Chemistry 2009 Chem. Commun., 2009, 2625–2636 | 2627

walker machine48 whose working mechanism is shown in

Fig. 4. Their device consists of two parts: a three-step track

and a biped walker. The track itself is in fact a triple crossover

(TX) molecule49 with three single-stranded overhangs

which serve as ‘‘footholds’’. The biped region has two duplex

‘‘legs’’ and on the end of each leg there is a single-

stranded ‘‘foot’’. Three additional single-stranded linkers

between the two legs make the biped walker flexible. A foot

attaches to a foothold when a ‘‘set’’ strand complementary to

both is added. The biped region will walk on the track in a

certain direction if specific set and unset strands are added

sequentially.

Shin and Pierce have proposed another simple approach for

a DNA walker.50 Their device has also two main components:

a walker and a track which are both in duplex forms. The

walker is a partially complementary duplex with two single-

stranded overhangs as legs. The track consists of six oligo-

nucleotides and has four protruding single-stranded branches.

With the similar walking principle to Seeman’s device, the

walker can move on the track by set and unset strands.

The above two DNA walkers, although their structures are

different, have similar working mechanisms. One of their

common features is that the walking steps in a certain direc-

tion is limited to the number of footholds or branches on the

track. We could imagine if the track is a circle rather than a

line, the walker may always move unidirectionally. This kind

of motion has been realized in a DNA nanogear model by

Mao’s group.51 The gear system has two DNA duplex circles.

Each circle contains four oligonucleotides and three single-

stranded overhangs as ‘‘teeth’’. These two circles may roll

against each other driven by the ‘‘fuel-strands’’ mechanism

which was also applied in the above two DNA walkers.

Evolution of kinetics and driven modes

One of the critical issues involved in all kinds of nanomachines

is how to control their motions precisely. In natural systems,

the sophisticated motions of protein-based nanomotors are

the results of complicated biological cooperations, and natural

evolution makes these machines work at their best. For most

DNA-based nanomachines, motions are generated from DNA

hybridizations. So the question now should be how to evolve

the kinetics and efficiency of the hybridizations in the DNA

nanomachines. Basically, many factors such as the machine’s

structure, environment, fuel and control mode will have

certain impacts.

Evolution of hybridization kinetics of ‘‘fuel-strands’’

The ‘‘Fuel-strands’’ strategy was first established in DNA

tweezer work by Yurke et al.30 In that work, both opening

and closing of the machine are controlled by the added fuel

DNA. The fuel strand will at first hybridize with a dangling

end; then displace an entire strand through branch migration.

This strand-exchange reaction is spontaneous and fast so the

kinetics of both opening and closing processes can not be

controlled. As a result, free fuel and anti-fuel strands can not

exist in the same system and they must be added step by step.

With the purpose of kinetic control of the DNA hybridiza-

tion process, Turberfield et al. proposed an ingenious strategy

of using a partially complementary protective strand to

pre-hybridize with the fuel strand (Fig. 5A).52 The particular

character of this pre-hybrid is its internal loop structure. The

authors have proved that this metastable loop structure is

effective in inhibiting the hybridization between the protected

fuel strand and free anti-fuel strand. This strategy is exciting

because the fuel and anti-fuel strands now can coexist in the

same system, which means that all DNA strands, including

machine and fuels, could be mixed together in a batch to start

the motion. In other words, this creates the opportunity to

design autonomous DNA-fuelled nanomachines. In their

work, the machine itself has been regarded as a ‘‘catalyst’’

whose function is to accelerate fuel and anti-fuel hybridiza-

tion. In the first step, protected strand can be displaced by the

catalyst strand to open the loop. In the next step, anti-fuel will

displace catalyst. Finally, the reaction releases waste product

(fuel/anti-fuel duplex and protected strand) and the catalyst

returns to the random coil state. This three-step reaction will

repeat as long as fuels are available. The loop structure has

been studied in detail in another work to clarify its function

and interactions with other strands.53

In an extended work,54 Seelig and Winfree et al. improved

the catalyst system by more than two orders of magnitude.

This was achieved by using two protective strands for both

fuel and anti-fuel strands and a ‘‘kissing loop’’ is necessary for

their system. The concept of ‘‘catalyst’’ has also been used in

works about speeding up a G-quadruplex nanomachine55 and

building DNA-based cascaded circuits.56

Recently, Pierce et al. has accomplished a unidirectional

hybridization driven polymerization motor (Fig. 5B).57 In

Fig. 4 A DNA biped walker. The track is drawn in blue and the

walker is drawn in brown. Matching colours indicate complementary

sequences between strands. The walker could walk on the track step by

step in a certain direction controlled by set and unset strands

(reprinted with permission from ref. 48; copyright 2004, American

Chemical Society).

2628 | Chem. Commun., 2009, 2625–2636 This journal is c The Royal Society of Chemistry 2009

their design, two metastable hairpin molecules are used as

fuels and the initial machine is a duplex. By mixing the

machine and fuels, the duplex will be broken and strand A

binds to H1 fuel (State 1), initiating a four-way branch

migration in which R is passed from A to H1 (State 2). H2

then binds to the newly exposed sticky ends (State 3) and R-H1

duplex is displaced by R-H2 duplex. The R strand will always

move away from the A strand autonomously in the presence of

fuels. The motion of this system mimics bacterial pathogens.58

It is intriguing that no preformed track is required and

the growing duplex may provide a track for other DNA

nanomachines.

Enzyme-assisted DNA nanomachines

Enzymes are natural catalysts for many DNA-based reactions.

It is possible to use enzymatic reactions to control the struc-

ture of DNA and make DNA mechanical devices.

The first enzyme-assisted DNA nanomachine was reported

by Mao’s group in an autonomous DNA motor.59 Their

machine consists of two strands (E and F) shown in

Fig. 6(a). The E strand contains an RNA-cleaving DNA

enzyme. The S strand is a DNA–RNA chimera which is the

substrate of the enzyme of E. Upon binding, the machine will

be opened by the SE duplex. The DNA enzyme E cleaves its

substrate S into two short fragments which have a lower

affinity for the E strand than the intact substrate and will,

therefore, dissociate from the machine. Its open and closed

states transitions could be switched autonomously by the

enzymatic reaction. The machine could be temporarily

stopped by adding brakes.60 Recently Bishop et al. have

Fig. 5 Autonomous DNA nanomachines. (A) DNA ‘‘catalyst’’

system. In this design, machine (catalyst strand) undergoes three

continuous steps of motions: hybridization, dehybridization and

release. The whole process will repeat unless all fuel strands have been

used up (reprinted with permission from ref. 52; copyright 2003,

American Physical Society). (B) An autonomous polymerization

motor. The metastable fuel hairpins (H1 and H2) do not interact in

the absence of the AR complex. Upon mixing, H1 binds to the sticky

ends of AR (State 1), initiating a four-way branch migration in which

R is passed from A toH1 (State 2).H2 then binds to the newly exposed

sticky ends (State 3) and R is passed from H1 to H2 (State 4). In this

manner, the R strand is passed back and forth between H1 and H2

hairpins at the living end of the growing polymer, moving away from

the A strand (reprinted with permission from ref. 57; copyright 2007,

Nature Publishing Group).

Fig. 6 Enzyme-assisted DNA nanomachines. (A) An autonomous

DNA nanoswitch powered by a DNA enzyme. The E strand contains

an RNA-cleaving DNA enzyme and its substrate is an S strand. The

cleavage of S will induce the closing of the machine. E will bind with

another S strand and open the machine again in the next step

(reprinted with permission from ref. 59; copyright 2004; Wiley Inter-

science). (B) An enzyme-controlled DNA walker. The track consists of

three evenly spaced duplex–DNA anchorages, A, B and C. A special

part which is drawn in red is the walker. Initially, A* which carries the

walker part will be ligated to B and then the duplex will be cut by

endonuclease. The walker part has thus been transported to B. In a

similar manner, the walker could be further transported to C

(reprinted with permission from ref. 62; copyright 2004; Wiley

Interscience).

This journal is c The Royal Society of Chemistry 2009 Chem. Commun., 2009, 2625–2636 | 2629

developed a method for improving its efficiency by using the

enzyme ribonuclease H to selectively digest waste.61

The enzyme-assisted method could be extended to make

DNA walkers. Three different approaches have been reported

up to now. One of these is controlled by ligase and endo-

nuclease as studied by Yin et al. (Fig. 6(b)).62 This device also

contains two components like other DNA walkers: the track

and the walker. The track is a long duplex with three short

duplex anchorages. The walker part is a six-nucleotide

fragment which is always covalently linked to anchorages.

Initially, the walker is on anchorage A. A step of this machine

could be divided into two half steps: firstly, the walker’s sticky

end will complement with anchorage B and be ligated to B by

T4 ligase; endonuclease PflM I then recognizes the newly

formed reorganization site and cuts the strand. As a model

and regardless of the length of the track, this machine could

walk autonomously and unidirectionally along a track.

The other two examples of enzymatic DNA walkers are

similar in walking mechanisms, but with different enzymatic

principles. The work done by Mao’s group is based on the

DNA enzyme.63 The track in their work is a long duplex

with single-stranded DNA–RNA chimera protrudings as

anchorages. A DNA enzyme-contained sequence is used as

the walker. When the walker binds to a anchorage, it will cut

the anchorage and move to the next one. The machines in this

case are also autonomous and unidirectional. A striking

feature is its ability to move infinitely if anchorages are

available. In another approach,64 Bath et al. employed restric-

tion endonuclease to cut the anchorages the make the walker

move, which will generate the same result as Mao’s design.

Evolution of kinetics by changing environment

Environmental factors play an important role in the move-

ments of DNA nanomachines. For example, a change in pH in

solution will induce the motions of i-motif and triplex based

DNA nanomotors. The key parts of these proton-driven

nanomachines are pH-sensitive DNA segments (C-rich

strands) which will be in folded and unfolded states, respec-

tively, under different pH values. It is interesting to speculate

that if the pH changing in solution could be controlled by a

coupled system, the kinetics of proton-driven DNA nano-

machines would be managed. In 2005, Liedl and Simmel

reported such an approach of controlling an i-motif DNA

motor65 by a chemical oscillator. As shown in Fig. 7, strandM

(M has the same sequence, except end modifications, with X in

Fig. 3) would undergo conformational switches between four-

stranded i-motif and single-stranded random coil structures

reversibly and periodically, driven by a pH oscillator in a

semibatch reactor. The pH oscillator in this case is a variant of

the Landolt reaction.66 The alternating oxidation of sulfite and

thiosulfate by iodate is accompanied by a periodic production

or consumption of protons. This oscillation reaction varies the

pH value between 5 and 7 periodically and then leads to DNA

conformational switches. A feed solution for the oscillator is

pumped slowly and continuously into the system, which also

brings a disadvantage as the oscillator will die out after several

cycles as a result of the continuous decrease in reactant

concentrations. Anyhow, this design of coupling pH oscillator

has shed light on making autonomous proton-driven DNA

nanomachines.

For DNA nanomachines powered by strand-exchange

reaction, the output and frame strength of the machines

depend on the stability of DNA hybrids, while the quick

response relies on hybridization speed. It is difficult to satisfy

both requirements simultaneously because usually they

will contradict each other. Maruyama’ group developed a

cationic copolymer-assisted strategy to solve such a problem

using G-quadruplex and DNA tweezer nanomachines as

models.67,68 The strategy is partially an extended work of their

previous studies on interactions between cationic comb-type

copolymers and triplex69 and duplex70 DNA. In those studies,

they found poly(L-lysine)-graft-dextran (PLL-g-Dex) copoly-

mers have special functions of accelerating strand-exchange

reaction while stabilizing DNA hybridization. Similarly, the

addition of PLL-g-Dex to the G-quadruplex nanomachine

system will increase opening and closing rates by 70- and

40-fold, respectively, while boosting the motion efficiency. For

DNA tweezers, the performance could also be improved by

PLL-g-Dex copolymers.

Non-contact control modes

The development of non-contact control modes, such as light-

and electricity-control, for stimulating DNA nanomachines

is a critical challenge. Non-contact systems offer distinct

advantages to contact modes controlled DNA nanomachines

in terms of simplifying the experiment by freeing our hands

from adding fuels manually and improving the efficiency and

precision of the machine by eliminating manual errors, making

it possible to perform complicated motions and communicate

with other nano-objects. Although light- and electricity-

controlled chemical nanomachines have already been

achieved,17–20 it is not easy to extend these strategies to

DNA-based machines since natural DNA is insensitive to

those stimuli. Basically, in terms of non-contact control of

Fig. 7 DNA conformational switches between the i-motif and

ssDNA driven by a chemical oscillator. In one-half of the reaction

cycle, protons produced during the oxidation of sulfite induce the

formation of the i-motif. In the other half of the reaction cycle, the

oxidation of thiosulfate consumes protons and leads to ssDNA

(reprinted with permission from ref. 65; copyright 2005, American

Chemical Society).

2630 | Chem. Commun., 2009, 2625–2636 This journal is c The Royal Society of Chemistry 2009

DNA nanomachines, there are only two routes we can evisage:

the first route is using artificial DNA strands which contain

light or electrical responsive modifications; the second route is

switching the environment by external non-contact stimuli.

These two routes have both been realized recently.

Asanuma’s group reported light-controlled DNA tweezers

with covalently tethered azobenzene moieties on the fuel

strand.71 Since the azobenzene group is sensitive to light

irradiation and its photoresponsive trans- and cis-isomers have

different stacking abilities with DNA base-pairs, the stability

of azobenzene-containing DNA duplexes and triplexes could

be regulated by UV and visible light. They have proved in their

previous work that the planar trans-azobenzene could inter-

calate between adjacent base-pairs and stabilize the duplex or

triplex structure by stacking interactions, whereas the non-

planar cis-azobenzene would destabilize it by steric hindrance.

In their design of DNA tweezers, 12 azobenzene groups have

been incorporated into the fuel strand. Under the alternate

irradiation of UV and visible light, azobenzene moieties are in

the cis- and trans-configurations, respectively. Therefore, the

stability of DNA duplex formed by the tweezer overhangs and

fuel strand could be switched. The tweezers will open in UV

light and close in visible light.

The above route needs specific modifications of DNA

strands, which brings difficulty in DNA synthesis. For natural

DNA, the second route mentioned above may be more

effective. In 2007, our lab first reported an approach of

controlling DNA conformational switch between the i-motif

and ssDNA structures by light (Fig. 8).72 MGCB is a photo-

chromic molecule which could generate a hydroxyl ion under

UV light with the reverse process occurring in the dark. By

turning on/off the UV light, MGCB molecules produce cycles

of pH jumps in solution. Since the DNA conformational

switch in our system is pH-sensitive, the coupling of a light-

induced pH jump system will realize DNA conformational

switches controlled by light. An advantage of this strategy is

that we do not need any modifications on DNA. Both ours

and Asanuma’s work used light as control signals and so do

not produce wastes.

Functional evolution of DNA nanomachines

What complicated work can DNA nanomachines do is a very

interesting question. Basically, there are several requirements

for DNA nanomachines to do practical work: (1) the

machine’s motion must be stable and powerful; (2) the opera-

tion should be simple and clean; (3) the machine should be

coupled to the object which is going to be driven.

Constructing switchable surface

Although a single DNA nanomotor could only generate a

force at the pN level, the possibilities for the cooperative

motions of many such motors, is clearly of importance. An

approach to test this cooperative effect is by immobilizing

DNA nanomotors on a surface.

Liu and Zhou et al. reported the immobilization of i-motif

DNA nanomotors onto defined locations of a microstructured

surface to form a microarray.73 Based on the conventional

thiol–gold interaction, the authors coupled thiol-modified

DNA motors to an Au surface, while the other end of each

DNA motor has a fluorophore modification. Then patterns

have been constructed on the above DNA monolayer. The

results demonstrated that the motor function was maintained

on the surface and an on-off optical switch, which is the result

of the cooperative work from numerous motors, could be

produced by changing pH. The working mechanism is that

under different pH values, the distance between the fluoro-

phore and Au surface could be switched, leading to different

FRET efficiencies. In a similar work, Simmel et al. utilized

their improved pH oscillator system to control the pH

switch.74 This work realized the autonomous switching of

surface optical signals for many cycles. The ability of

controlled immobilization of DNA motors on a defined sur-

face is an important first step towards the construction of

complicated nanodevices.

Based on the above work, it is possible to switch the surface

function by DNA nanomotors in response to stimuli. Fig. 9

shows the effort of switching surface wettability by three-state

i-motif DNA nanomachines.75 The DNA nanomotors were

coupled to a gold surface through thiol–Au bonds and a

hydrophobic Bodipy-type fluorophore was attached on the

other end of the DNA strand. At low pH (state I), DNA

motors are in the closed states and hydrophilic phosphate

backbones of DNA strands are exposed, leading to a hydro-

philic surface. By raising the pH (state II), DNA motors will

adopt ssDNA forms and the Bodipy groups will no longer be

concealed. Therefore the surface will be switched to hydro-

phobic wettability. The state II is not stable for long time since

it is a loosely disordered state. The addition of complementary

strands of DNA motors could help DNA adopt rigid duplex

conformations and make the monolayer be closed packed

(state III). At this state the hydrophobic behaviour is stable.

It is interesting to note that a rough surface could enhance

surface wettability, either hydrophilicity or hydrophobicity.76

Fig. 8 DNA conformational switches between i-motif and ssDNA

controlled by light irradiation. Inner cycle: the DNA conformational

switch between the i-motif and ssDNA. Outer cycle: the light-induced

pH jump. The conformational switch of DNA X is associated with the

on and off phases of UV light (reprinted with permission from ref. 72;

copyright, 2007, Wiley Interscience).

This journal is c The Royal Society of Chemistry 2009 Chem. Commun., 2009, 2625–2636 | 2631

In our system, switches between superhydrophilic and super-

hydrophobic wettabilities could be produced by DNA

nanomachines on rough substrates.

Directing chemical reactions

DNA-templated chemical synthesis77–79 is a strategy that

could select targets and increase the effective molarity of

DNA-linked reactants by sequence-specific DNA hybridiza-

tion. The utilization of DNA nanomachines could exert

remarkable controllability to trigger the synthesis process.

Based on pH-driven triplex–duplex DNA nanodevices,

Chen and Mao realized switching chemical reactions between

two identical reagents.80 In response to the change of solution

pH, the DNA device changes its conformation and repositions

chemical reagents that are conjugated with DNA strands. As a

result, chemical reactions are reprogrammed.

Other than most DNA nanomotors which generate

open–closed type motions, the PX–JX2 machine 34 developed

by Yan and Seeman could exert robust rotations between its

two topological states PX and JX2. By incorporating two

PX–JX2 machines in succession, its motions will produce four

different combinations: PX1–PX2, PX1–JX22, JX21–PX2 and

JX21–JX22. In an attractive work carried out by Liao and

Seeman,81 they translated DNA signals of such a two-

successive PX–JX2 machine into polymer assembly instruc-

tions and obtained four ligated products. Their design mimics

the translational capabilities of the ribosome. In response to a

DNA signal (set strands for a specific combination of the

machine), the machine drives substrates (DNA motifs for

assembling polymer) to form a specific linear array; and aligns

a series of DNA strands (could be regarded as polymer) in

specific positions; these strands are then fused together in a

specific order. The products are DNA oligonucleotides of a

defined sequence. In theory, if N single PX–JX2 machines are

present, the number of combinations and assembled products

will be as large as 2N. This DNA machine-based translation

system has promising applications in directed assembly,

molecular computing, and encryption.

Programmable chemical reactions could also be performed

on an addressable DNA tweezer array.82 In a report from Yan

and co-workers (Fig. 10), three tweezers, each bearing two

coupling reactants, are self-assembled on a linear DNA track.

A fourth tweezer floating freely in solution can be bound to

any one of the tweezers and close them by the addition of a

unique pair of fuel strands. The coupling reactions occur when

the tweezers are closed, and this can be controlled sequentially

from one tweezer to the next.

Driving objects

For most DNA nanomotors, the force comes from the free

energy released by the DNA hybridization process. Actually,

even before the invention of the first DNA-based nano-

mechanical device,23 the concept that DNA hybridization

could be employed to drive nano-objects such as gold nano-

particles was already been proved by pioneering work of

Mirkin83 and Alivisatos.84 Niemeyer et al. realized reversible

switching of DNA–gold nanoparticle assembly by using

fuel-strands.85 DNA triplex-based gold nanoparticle reversible

assembly has been achieved by a proton-fuelled strategy.86

More recently, our87 and Yan’s88 groups have published our

approaches of making i-motif DNA nanomotors controlling

gold nanoparticle assembly. Also in work based on an i-motif

DNA motor, Li et al. demonstrated that its power can been

used to break certain forms of Watson–Crick interactions.89

We have demonstrated that the immobilization of numerous

DNA nanomotors on a substrate will generate a cooperative

effect which is able to change the surface property.75 Further,

the force generated from these immobilized nanomotors, has

Fig. 9 DNA nanomachine-controlled surface wettability switch. At

low pH, the DNA adopts an i-motif conformation (state I). Raising

the pH destabilizes the i-motif to produce a stretched single-stranded

state (state II) or a duplex structure (state III, when a complementary

strand is present). Lowering the pH induces a reverse conversion

process from state II or III to state I (reprinted with permission from

ref. 75; copyright 2007, Wiley Interscience).

Fig. 10 Addressable DNA tweezers for templated coupling reactions.

Three footers, F1, F2 and F3, link to the track containing a linear

array of DNA double crossover motifs. The red and blue dots

represent –NH2 and –COOH groups, respectively. By adding of a

specific pair of set strands, the header (H) can go to any footer on the

track, facilitating the formation of three specific amide bond coupled

products (reprinted with permission from ref. 82; copyright, 2006,

American Chemical Society).

2632 | Chem. Commun., 2009, 2625–2636 This journal is c The Royal Society of Chemistry 2009

been proved to be strong enough to drive objects much larger

than nanosized. As shown in Fig. 11, McKendry et al. have

shown it is possible to convert the force to bend micro-

cantilever arrays.90 Open-state i-motif DNA motors (in duplex)

were assembled on one side of a cantilever. By decreasing the

pH value the DNA motors will adopt i-motif forms. Upon

formation of i-motif structures, DNA motors will exert

repulsive in-plane surface forces (compressive surface stress)

which cause the cantilever to bend downward. The magnitude

of this surface stress has been measured as around 32 mNm1.

The bending process is highly reversible by switching DNA

motors. The origin of this surface stress has been attributed

mainly to electrostatic repulsions. The authors suggested that

both inter- and intra-molecular repulsions of the four-

stranded i-motif structure is higher than for the duplex form,

and therefore the compressive stress will induce the bending of

the cantilever to increase the available surface area. This work

first certified that the cooperative effect of DNA nanomotors

could generate a dramatic force large enough to drive even a

macroscopic object. The cooperation-based approach should

be applicable to other DNA nanomachines to amplify their

working abilities to the macroscale.

The evolution of the PX–JX2 machine has resulted in a

DNA nanorobot.91 As shown in Fig. 12, a cassette system

contains a PX–JX2 machine, an attachment site, and a report

hairpin, and many such cassettes have been incorporated into

2D DNA crystalline substrates to form arrays. Switching

PX–JX2 nanomachine states by set strands will induce the

rotation of a reporter hairpin. Since the 2D DNA lattice serves

as a fixed frame of reference, the rotations of reporters will

generate measurable directional displacements on the DNA

substrate. As monitored by AFM, the rotations of the hairpins

relative to the 2D DNA lattice could be easily visualized. The

appealing feature of this work is the realization of integrating

DNA nanomachines with DNA assembled nanopatterns. It is

expected that the DNA reporters could do practical work to

mimic robot arms.

A unique work noted in the final part of this section is a

DNA supercoiling based switching of DNA–nanoparticle

networks.92 Streptavidin (STV) particles have been used to link

DNA strands to form dsDNA–STV networks. Upon raising

the magnesium concentration in the system, DNA condensa-

tion (thickening and shortening) could be observed which is

probably due to a supercoiling motion of the DNA fragments.

As sensors

Sequence-specific DNA detection is very important in various

biomedical applications. The recent work of Crain’s group

has presented a new method to discriminate single-base

mismatches based on DNA nanoswitches.93,94 In their design,

the probe and target DNA will form a switchable four-way

Holliday junction. A remarkable characteristic of this complex

is its ability to switch in response to stimuli such as divalent

ions. It has been found that changes in the switching

characteristics of such a device can be used to differentiate

various targets. A 30-fold discrimination between single-

nucleotide mismatches in a DNA oligonucleotide could be

obtained. This method may be useful in single nucleotide

polymorphism (SNP) discrimination.

Willner’s group has contributed much work in DNA

machine based sensors in recent years. Fig. 13 shows their

work for detecting M13 phage ssDNA.95 In the presence of

target DNA strands, the hairpin will be opened and then

polymerization will be triggered. However, the polymerized

Fig. 11 Bending metallic microcantilever by DNA nanomachines. At

high pH the hybridization of surface-tethered X to strand Y in solution

forms the duplex structure. At low pH, X forms the self-folded i-motif

and induces repulsive in-plane surface forces (compressive surface

stress) which causes the cantilever to bend downward (reprinted with

permission from ref. 90; copyright 2005, American Chemical Society).

Fig. 12 DNA nanomachine-based nanorobots. Top: cartoons show

that the array is formed by eight triple crossover tiles. The cassette and

reporter helix are shown as solid red components and the black parts

are markers. Bottom: AFM images show that the positions of the

reporter hairpin (in red circle) in the PX and JX2 states are different

(reprinted with permission from ref. 91; copyright 2006, AAAS).

This journal is c The Royal Society of Chemistry 2009 Chem. Commun., 2009, 2625–2636 | 2633

duplex domain contains a N.BbvC IA recognition site which

will cause the nicking (scission) of the replicated single strand

and the resultant sequence will fold into a G-quadruplex

with an intercalated hemin molecule. The complex mimics

peroxidase activity and catalyzes an oxidation reaction. The

generation of chemiluminescence from this reaction could be

detected as an output signal. The obtained G-quadruplex

sequences could also be designed to induce nanoparticle

aggregation.96 Other work by this group includes constructing

sensors for detecting cocaine97 and mercury ions.98

Performing controllable release

Controllable collection/release of molecules or nanomaterials

is a critical issue for materials science, pharmaceutics, bio-

medical applications, and also for constructing hierarchical

nanodevices. The feature of generating a nanomechanical

output makes DNA nanomachines an ideal tool to trigger

such nanoscale processes. The challenge is the conversion of

mechanical force to signals for releasing targets. Up to now,

two strategies have been explored.

The first strategy is the direct utilization of the DNA

nanomachines’ force to change the volume of a nanoscale

container. Such a controllable DNA nanocontainer system has

been developed by our group in 2007 (Fig. 14(a)).99 The device

was implemented with the success of immobilization of DNA

nanomotors on a surface.73 The most distinctive characteristic

of this device is that each i-motif DNA motor in the assembled

monolayer is linked to the surface through a single stranded

poly-(dA)n spacer (10 r n r 35). The function of spacers in the monolayer is important since they provide a low-density

packing domain, which could be regarded as a nanocontainer.

By changing pH, the packing density of the upper domain

(DNA motors domain) could be switched between high

(densely packed i-motif conformations, closed state) and low

(loosely packed ssDNAs, open state) states. At open state,

small molecules could be released from spacer domains to the

outer environment, while at closed state these molecules would

be restricted in the nanocontainer protected by the upper

closely packed DNA motors.

The encapsulation ability of 3D DNA assembled

nanostructures100 have been studied by Turberfield’s group

Fig. 13 Detecting ssDNA targets by DNA nanomachine. M13 phage

ssDNA will hybridize specifically to a hairpin strand and then produce

a large amount of G-quadruplex structures. The intercalation of hemin

molecules to the G-quadruplex will catalyze an oxidation reaction

which will generate chemiluminescence (reprinted with permission

from ref. 95; copyright 2006, Wiley Interscience).

Fig. 14 DNA nanomachine based nanocontainers. (A) An i-motif

DNAmotors controlled nanocontainer. At low pH, the C-rich domain

folds into i-motif structure and packs into a membrane impermeable

for small molecules on a gold surface. At high pH, the i-motif

structures are transformed into ssDNA, making the packing density

relatively loose to allow small molecules to diffuse freely (reprinted

with permission from ref. 99; copyright 2007, Oxford Journals). (B) A

reconfigurable DNA tetrahedron. The tetrahedron is formed by four

strands and a hairpin segment has been incorporated into one edge.

Based on ‘‘fuel-strands’’ strategy, the hairpin can be switched between

open and closed states, leading to a volume change of the tetrahedron

(reprinted with permission from ref. 101; copyright 2008, Nature

Publishing Group).

2634 | Chem. Commun., 2009, 2625–2636 This journal is c The Royal Society of Chemistry 2009

using rigid DNA tetrahedra.15 The evolution of this strategy

has led to reconfigurable DNA tetrahedra whose shapes

change precisely and reversibly in response to specific

molecular signals.101 As shown in Fig. 14(b), a hairpin

segment has been incorporated into one edge of this new

reconfigurable DNA tetrahedron. The edge containing hairpin

is at its shortest (10 bp, 3.4 nm) when the hairpin is in the

closed state. By adding a fuel strand that opens the hairpin, the

edge could be extended to its longest state (30 bp, 10.2 nm).

This transition will cause a volume change. A tetrahedron with

two reconfigurable edges has also been built in this work.

The second strategy to control release by DNA nano-

machines is to exert force to break substrate–target interactions.

Simmel et al. have demonstrated this cyclically binding and

releasing thrombins by G-quadruplex based nanomachines.102

It is well known that the G-quadruplex structure has a high

binding affinity to the thrombin molecule. Using the same

strategy to open G-quadruplex nanomotors, the addition of

fuel-strands will disrupt the interactions between the

G-quadruplex and thrombin molecules to realize the release

of thrombins. The release kinetics has also been studied.103 In

a related work done by Sugiyama’s group,104 pH switching has

been employed to control the release of the telomere-binding

protein TRF 1 which has high affinity towards the i-motif

structure; or the release of small G-quadruplex-binding

molecules to impede progress of the polymerase.

Conclusions and outlook

In this review, we have summarized the development of DNA

nanomachines in recent decades. The development of this field

has demonstrated again the DNA is an important multi-

purpose material in nanotechnology other than its biological

characteristics.

Looking towards the future, the current research on

DNA nanomachines is still in its early stages and the most

established systems are simple models. We here consider the

following issues which might be the most important challenges

for future development in this field: (1) experimental and

theoretical studies on single DNA nanomachines leading to

understanding of energy conversion mechanisms and entropy

exchange with the environment; (2) a new power supplying

method which could be easily incorporated into current silicon

based nanodevices; (3) improvement of the reliability of DNA

nanomachines; (4) directionally controllable movements;

(5) multi-component DNA nanomachines with clear and

interconnected energy transformation and mechanical

response; (6) evaluation of biological and medical applications

of DNA nanomachines. In summary, the anticipated devel-

opment in this field will be fascinating and we believe DNA

will play a more important role in nanoscience in the coming

decade.

Acknowledgements

D. L. would like to thank Prof. Xi Zhang in Tsinghua

University for helpful discussion and NSFC under grant No.

20725309, NSFC-DFG joint project TRR61 andMOST under

grant No 2007CB935902 for financial supports.

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2636 | Chem. Commun., 2009, 2625–2636 This journal is c The Royal Society of Chemistry 2009

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