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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
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.
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
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: email@example.com; Fax: +86-10-62656765; Tel: +86-10-82545589
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.
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,
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
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
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.
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
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
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
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
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
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
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
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
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
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.
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.
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
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
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
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