Perspective
pubs.acs.org/JACS
Chemically Propelled Molecules and Machines
Krishna Kanti Dey*,† and Ayusman Sen*,‡
†
Department of Physics, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar 382355, Gujarat, India
‡
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
ABSTRACT: Self-propelled, synthetic active matters that
transduce chemical energy into mechanical motion are
examples of biomimetic nonequilibrium systems. They are
of great current interest, with potential applications in
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nanomachinery, nanoscale assembly, fluidics, and chem-
ical/biochemical sensing. Many of the physical challenges
associated with generating motility on the micro- and
nanoscale have recently been overcome, leading to the first
generation of autonomous motors and pumps on scales
ranging from microns to nanometers. This perspective
focuses on catalytically powered motile systems, outlining
major advances to date in motor/pump design, propulsion
mechanisms and directional control, and intermotor
communications leading to collective behavior. We con-
clude by discussing the possible future directions, from the
fundamental questions that remain to be addressed to the
design principles required for useful applications.
■
INTRODUCTION
We live in the information age, driven by the ability to com-
municate and integrate ideas. However, this is also the age of
miniaturization, with the ability to fabricate, manipulate, and
assimilate matter on the nanoscale facilitating the information
exchange.1−3 While we have become quite adept at fabricating
materials on the small scale and manipulating the flow of
energy through them, the ability to precisely control the motion
of the materials themselves is still in its infancy. Until recently,
the work in this area has mostly focused on coaxing micro- and
nanostructures to deform, rotate, and move repeatedly over
well-defined molecular-scale distances.4−7The pioneering work
in this area has led to the award of the 2016 Nobel Prize in
Chemistry to Savage, Stoddart, and Feringa.8 This perspective
focuses on a complementary, and arguably more challenging,
avenue of research: How can we design populations of arti-
ficial micro- and nanostructures that can move autonomously
over long distances, while at the same time have the ability to
organize themselves on command to perform complex tasks.
The potential applications of such synthetic interacting nano
and micromachines would be almost limitless. Access to ratio-
nally designed dynamic materials that are capable of remodeling
themselves and transforming their environment will (i) mini-
mize waste (they will change their function and purpose rather
than being of single-use), (ii) improve performance (they will
continuously evolve their structures to optimize performance),
and (iii) accomplish tasks collectively and emergently (like a
colony of ants) that a single constituent element (like a single
ant) cannot perform. By making these dynamic materials
self-powered, they can be made capable of exploring and
© 2017 American Chemical Society
responding to their environment (sensor applications) without
being tethered to a single power source or location. In this
perspective, we focus on chemically powered motors and
pumps at submicroscopic length scales. Motors are objects that
can transduce chemical energy into mechanical motion through
a variety of propulsion mechanisms. When these motors are
anchored onto a surface, their mechanical energy is transferred
to the surrounding fluid, making them function as miniaturized
fluid pumps.
■
NANOMOTOR DESIGNS: CHALLENGES AT LOW
REYNOLDS NUMBER
In the natural world, controlled motion at the nano and micron
scale is ubiquitous. Motor proteins power the motion of
bacterial flagella and cilia, facilitating the movement of these
tiny organisms through solutions.9 Some bacteria use short,
hair-like appendages known as pili for movement, that binds to
the host surface receptors and when retracted, pull the bacteria
along the surface.10 Active ion pumps inside the cellular interior
constantly transcribe chemical information by transporting
various ions against chemical potential gradients; maintaining
proper balance in intracellular osmolyte concentrations.11
Evolutions, however, had millions of years in optimizing the
extraordinary range of biological innovations and tools. Lacking
the luxury of time, we must take advantage of our ability to
intelligently design potential motors. In such a task, we must
consider the nature of physical laws operative at low Reynolds
number regimes and their consequences on fluid motion and
particle dynamics. Physics at submicroscopic length scales is
usually dominated by shear forces parallel to particles’ surface
rather than by inertial forces which scale with particles’ volume
and which dictate their dynamics at the macroscale.12 Propul-
sion at micro- and nanometer length scales can therefore be
achieved effectively by generating various shear force gradients
across the particle surface. Additionally motions of tiny particles
in fluids are influenced by Brownian forces, which results in
erratic random walk like trajectories at longer time scales.13 The
biological world is dominated by random thermal fluctua-
tions but nature has developed machines that can rectify the
fluctuations to do useful work (e.g., Brownian ratchets such as
F0 motor in ATP synthase or actin).14 Molecules of kinesins
and dyneins move along microtubules, and certain myosins are
designed to move along actin filaments by overcoming the
strong Brownian fluctuations, driving the intracellular traffic of
vesicles and organelles with remarkable efficiency.15 Finally,
several physical forces, which are negligible across long dis-
tances, begin to dominate on the nanoscale. Electrostatic forces
Received: March 8, 2017
Published: May 11, 2017
7666 DOI: 10.1021/jacs.7b02347
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Journal of the American Chemical Society
between charged objects, for instance, grow proportional to
ΔR2 as the distance between objects is decreased. The (usually
attractive) van der Waals interactions between an object and
its neighbors, on the other hand, grow by ΔR6.16 This is the
basis for the “sticky fingers” argument as to why it is physically
impossible to build nano robots that reproduce themselves
through atom by atom assembly.17
Nature of fluids at smaller length scales offers additional
challenges in designing propulsion strategies for nanomotors.
The systems are characterized by very low Reynolds num-
bers, and to achieve propulsion, it requires swimmers to
deform in a way that is not invariant under time reversal. The
Reynolds number (Re) of the particle, which is usually mea-
sured as the ratio of inertial to the viscous force, can be
expressed as18
ρVL
Re =
μ (1)
Here, ρ is the density of the fluid, V is the velocity of the
particle relative to the fluid, L is the characteristic length
scaleusually considered to be the dimension of the particle,
and μ is the viscosity of the fluid. One far reaching consequence
of low Re limit is kinematic reversibility, which facilitates lam-
inar flow of liquids within narrow confinementsa property
that has been extensively exploited in microfluidic devices.19,20
This has further been demonstrated by the famous Couette cell
demonstration,21 where a drop of dye suspended in a high
viscosity liquid is sheared between two concentric cylinders and
stretched to wrap around the inner cylinder several times. The
motion is then reversed which brings back the drop of dye to its
original shape. This is famous Scallop theorem of Purcell22 and
microscopic swimmers overcome this hurdle by many fascinat-
ing swimming strategies that break the time reversal symmetry
at low Reynolds number. This is very different from the macro-
scopic world where owing to the dominance of inertial motion,
reciprocal swimming strategies can lead to effective propulsion
of objects in fluids.
■
MECHANISMS OF MOTILITY AT MICRO- AND
NANOMETER LENGTH SCALES
Micro and nanoscale colloidal particles often have a few
molecular layers of fluid pinned over their surfaces by strong
van der Waal’s forces, resulting in what is known as the no-slip
condition.23 Beyond this pinned layer, charged colloids are
usually surrounded by a cloud of counterions forming what is
known as the interfacial or double layer. The thickness of
interfacial layer is decided by the particle surface charge and the
local ionic strength of the medium, and is normally measured in
terms of the Debye length (κ−1 by convention) of the particle,
which in most systems lies within 1−100 nm.24 The Debye
length can be calculated from eq 2,13
ε0εrkBT
κ −1 =
2NAe 2I (2)
where ε0 is the permittivity of free space, εr is the dielectric
constant of the electrolyte, kB is the Boltzmann constant, NA is
Avogadro’s number, e is the charge of an electron, and I is the
solution ionic strength.
Each particle together with its interfacial layer is electrically
neutral and, without any external field, is in equilibrium. How-
ever, they can be set into motion by a variety of external fields
and most motility mechanisms involves generation of asym-
7667
Perspective
metric force fields of some nature around each particles in an
assembly. In the presence of local force fields, the mobile ions
within the interfacial layer of each particle move and cause
liquid flow, making the particle drift in the opposite direction.
Motions of this kind which arises due to forces operating within
the interfacial layer of the particles, rather than on the bulk are
called phoresis. Molecules and microparticles, capable of
chemically interacting with their surroundings have recently
been shown to self-propel using different phoretic mecha-
nisms.25−27 As described below, this offers a range of possi-
bilities to maneuver micro- and nanoscale particles in liquid
independently, while simultaneously endowing them with
specific functionalities in an assembly.
■ ELECTROPHORESIS
Electrophoresis results when motion is induced in colloidal
particles using electric fields. Dynamics of freely diffusing ions
can also be influenced by external electric fields. For larger
colloids, however, the mobile ions within the interfacial layer of
a particle interact with the electric field, resulting in fluid flow
around the particle surface. The fluid flow together with
particle’s own electrostatic interaction with the field causes a
steady drift of the particle with respect to the fluid layer. The
electrophoretic speed of the particle can be calculated from the
magnitude of the electro-osmotic flow around it, using the
famous Smoluchowski equation:16
εζ E∞
U=
η (3)
Here ε is the permittivity of the solution, ζ is the zeta potential
of the particle, η is the viscosity of the solution and E∞ is the
electric field. The electric field can be external or generated
in situ through redox chemical reactions.
Self-electrophoresis has been demonstrated by several groups
working on motors of different compositions and geometry.28−35
The initial Pt/Au nanorod motor discovered by Paxton et al.
functions based on self-electrophoresis (Figure 1), where
Figure 1. Schematic of Pt/Au bimetallic nanomotor fabricated by
Paxton et al.28,30 The rods self-electrophoretically move in hydrogen
peroxide solution by redox reactions occurring at their ends. Figure
adapted from ref 30 with permission from the American Chemical
Society.
catalytic decomposition of hydrogen peroxide results in the
generation of an electric field, powering the nanorods.28,30
Mano et al. fabricated a bioelectrochemical motor by attaching
two electrochemically coupled enzymes to the opposite ends of
a carbon fiber.35 Several factors influence self-electrophoretic
motility of particles including the fluid medium, solution
viscosity and ionic strength.36
■ DIFFUSIOPHORESIS
The generation of ionic products by catalytic particles in a
liquid has additional effects on the particle double layer. First,
spontaneous electric field generated within the liquid by the
diffusing ions can result in electrophoresis of the particles.
Moreover, as mentioned earlier, the thickness of double layer
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varies inversely with the local ionic strength and the gradient
of an electrolyte can polarize the counterion cloud around a
particle. Such polarization causes ions from the higher solute
regions to migrate across the particle toward the other end,
generating a fluid flow within the double layer. The particle
in consequence, will drift steadily toward the higher solute
regions. Particle drift toward higher solute regions, arising only
as a result of double layer polarization is known as chem-
iphoresis. The combination of self-electrophoretic and chemi-
phoretic effects leads to an overall diffusiophoretic interfacial
flow, which powers the movement of particles.37−40 Depending
on the nature of the solute added, diffusiophoresis can be
classified into two categories: (a) ionic diffusiophoresis, trig-
gered by an electrolyte38 and (b) nonionic diffusiophoresis,
triggered by a nonelectrolyte.37 For diffusiophoresis in a mono-
valent electrolyte, the propulsion speed can be approximated by
eq 4.38,39
⎧ ⎫
⎪ ⎪
⎪ εζ kBT ⎛ DC − DA ⎞ ε ⎛ kBT ⎞
2
⎪
U = ⎨− ⎜ ⎟+ ⎜ ⎟ ln(1 − ξ ) ⎬
2
4πη e ⎝ DC + DA ⎠ 
⎪  ⎝ e ⎠

2πη
  ⎪
⎪ ⎪
⎩ electrophoresis chemiphoresis ⎭
d ln C
dx (4)
where U is the particle velocity, kB is the Boltzmann constant, T
is temperature, η is the viscosity of the solution, e is the charge
of an electron, d ln C is the gradient of the electrolyte, DC is the
dx
diffusion coefficient of the cation, DA is the diffusion coefficient
of the anion, ζ is the zeta potential of the particle surface and
ξ = tanh ( )eζ
4kBT
From the above discussion, it follows that gradient of an
electrolyte imparts motion in colloidal particles independently
through two distinct ways. Chemiphoresis arising out of
interfacial layer polarization always directs particles toward
higher solute concentrations.41 However, the direction of the
electrophoretic propulsion depends on the nature of particle’s
zeta potential as well as on the relative diffusivities of the ions
(DC and DA for cations and anions, respectively) produced as a
result of the dissociation of the electrolyte. The resultant
particle speed in ionic diffusiophoresis therefore, can be
estimated by summing up these contributions. The diffusio-
phoresis propulsion mechanism can lead to many biomimetic
collective emergent patterns, which will be discussed later.
Gradient of neutral molecular solutes can also induce pro-
pulsion in colloidal particles with specific directionality.
Molecules of a nonelectrolyte usually interact with the particle
surface with short-range van der Waal’s forces. In nonionic
diffusiophoresis, colloidal particles move toward regions of
higher or lower solute concentrations depending on the nature
of solute-particle interaction. Velocity of a rigid spherical par-
ticle in the presence of a nonelectrolyte gradient, which is
assumed locally parallel to the particle surface, was quantified
by Anderson et al. as37,39
kT
U = B KL*
dC
η dx (5)
Here, dC is the magnitude of the unperturbed solute gradient,
dx
L* is a measure of the range of particle-solute interaction.
7668
Perspective
The parameter K is known as adsorption length, which physically
signifies the strength of particle-solute interaction.
Nonionic diffusiophoresis can also propel particles that
generate local solute gradients via chemical reactions. Possible
nonionic self-diffusiophoretic motion was demonstrated by
Pavlick et al., where gold/silica Janus particles, coated with a
polymerization catalyst on the silica face, exhibited enhanced
diffusive motion in a solution of monomers.42 The polymeriza-
tion reaction occurring on one face of the particle created a
concentration gradient of the monomer across the particle
surface. The gradient generates an interfacial fluid flow toward
higher concentration of monomers (Au face), eventually pro-
pelling it with the catalyst end forward (Figure 2). Over longer
Figure 2. Schematic showing the propulsion mechanism of the
polymerization powered motor. Fluid flow from low to high monomer
concentration regions causes the motor to move with the catalytic end
forward.42 Figure adapted from ref 42 with permission from John
Wiley and Sons.
time scale, the motion however remains diffusive. Interestingly,
there are systems where the inverse mechanism has also been
realized. By asymmetric catalysis, the particles generate gradient
of product molecules across their surface, which propel them in
solution with their noncatalytic end forward.43−45 Powered
motion of Pt/Si Janus particles is believed to follow this
mechanism. The catalytic Pt side of the motor decomposes
hydrogen peroxide into water and oxygen, which leads to the
creation of an oxygen gradient across the particle surface,
setting it into motion.45
One of the major advantages of powering nanomotors with
nonionic self-diffusiophoresis is that it can propel particles in
high ionic strength media. Electrolyte diffusiophoresis being
dependent on total ion concentration, is not effective in high
ionic strength media due to the collapse of interfacial layer on
the particle surface. However, in low ionic strength solutions,
ionic diffusiophoresis is always more powerful and can result in
much higher propulsion speeds than the nonionic counterpart.
This is due to the fact that both nonionic diffusiophoresis and
chemiphoretic part of ionic diffusiophoresis originates from
similar sourcesasymmetries in solute concentrations across
the particle surface. Their contributions toward the net propul-
sion speed is therefore of the same order of magnitude. The
additional self-electrophoresis component in ionic diffusiopho-
resis however augments the propulsion speed making it stronger
propulsion mechanisms in low ionic strength conditions (eq 4).
■ COLLECTIVE DYNAMICS OF
SELF-DIFFUSIOPHORETIC MOTORS
Many microorganisms in nature use chemical signals derived
from each other to communicate and accomplish specific tasks
collectively. An example is chemotaxis which involves organisms
moving up or down a chemical gradient.46,47 The cells of
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Dictyostelium discoideum show robust chemotactic response
upon sensing the signaling chemical 3′-5′-cyclic adenosine
monophosphate (cAMP). cAMP is secreted when the cells are
starved and chemotaxis leads to their aggregation into a
migrating slug, which then differentiates into a multicellular
fruiting body.48−50 The key aspect of this collective behavior is
that these organisms both produce and respond to cAMP
trigger for surviving harsh conditions of nutrient depletion.
Purely synthetic inorganic systems can also display similar col-
lective dynamics. Micron-sized silver chloride (AgCl) particles
dispersed in deionized water collectively move under UV illu-
mination in response to self-generated ion gradients (Figure 3).51
Figure 3. Schematic showing photocatalysis of AgCl particles resulting
in the formation of H+ and Cl− ions. Higher diffusivity of H+ than that
of Cl− generates an electric field to which the nearby particles respond
and move with a diffusiophoretic speed Udp. The electric field also
influences ions within the double layer of nearby surfaces creating fluid
flow with diffusioosmotic speed Udo.51 Figure adapted from ref 51 with
permission from Royal Society of Chemistry. With sufficiently high
number density, the particles respond to each other’s ion gradients,
forming macroscopic schools (shown in Figure 4 below).52
Like Dictyostelium discoideum, each AgCl particle secretes
the chemoattractant in the form of H+ and Cl− ions as it
moves, to which the other particles respond and modulate
their dynamics. This eventually forms “schools” of AgCl par-
ticles, mimicking the slime mold’s behavior in two dimensions
(Figure 4).
An even more interesting dynamic behavior is observed with
a mixture of photo activated AgCl particles and silica micro-
spheres dispersed in deionized water. Upon UV illumination,
silica spheres respond to the ions secreted by AgCl particles
and actively surround them, displaying predator−prey behavior,
like that of neutrophils (Figure 5).53 Such long-range emergent
interaction in active particle assemblies offers new possibilities
Figure 4. Schooling behavior of AgCl particles in deionized water (A) before UV illumination, (B) after 30 s of UV exposure, and (C) after 90 s of
UV exposure.52 Figure reproduced from ref 52 with permission from John Wiley and Sons.
7669
Perspective
for designing smart nanomachines that can carry out specific
tasks collectively in complex environments. There are many
possible ways of designing ion-producing nano/microparticles,
including particles with attached catalysts or enzymes that form
ions as products. These particles should then interact with each
other or with inert nano/microparticles through their ionic
products. In addition, it allows coordinated and controlled
movement of particles that are not attached to each other,
which should find wide applicability in targeted material trans-
port and delivery.
■
TRANSITIONS BETWEEN COLLECTIVE BEHAVIORS
Apart from motility, colonies of microorganisms also display
novel transitions between different modes of collective behavior
in response to external stimuli. This provides motivation to
realize dynamic transitions in synthetic active systems, in order
to accomplish different tasks in succession with the same group
of multifunctional motors. Dynamic transition in active sys-
tems has been demonstrated in AgCl/UV system, when driven
by two different chemical reactions. Transition in collective
behavior occurs when H2O2 is added to the systemresulting
in periodic oscillations of particles.54 Two competing processes
are responsible behind the chemical clock. The reduction of
AgCl to Ag by UV light and the oxidation of Ag back to AgCl
by H2O2 produce and consume HCl, respectively, which leads
to periodic reversal of ion gradient. As a result, the AgCl par-
ticles exhibit an oscillatory attach−release motion with neigh-
boring silica spheres, as shown in Figure 6(a).
Using a reversible chemical reaction, transitions between two
modes of collective behavior has been demonstrated in system
involving silver orthophosphate (Ag3PO4) microparticles dis-
persed in dilute ammonia solution. The system reaches equi-
librium quickly and any subsequent addition or removal of
ammonia shifts the equilibrium, producing or consuming ions
that include fast-diffusing OH−. The assembly then transitions
between clustering and dispersion (Figure 6b).55 The transition
can also occur in response to UV light, and with two orthog-
onal stimuli, the behavior of the system can be used to design a
colloidal logic (NOR) gate (Figure 6c).
■ BUBBLE PROPELLED SYSTEMS
Propulsion induced in small scale machines by bubble recoil
is another widely investigated mechanism.56−62 Systems with
different geometries have been shown to display impressive
propulsion speeds following chemically generated bubble recoil.
The motion can be controlled using external (e.g., magnetic)
fields,63,64 which is ideal for certain applications where motors
must reach a destination quickly or move against opposing
fluid flows, e.g., blood, with varying speeds and forces. These
high speed motors are easy to design and can find useful
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Figure 5. Predator−prey behavior displayed by photoactivated AgCl particles and silica microspheres dispersed in deionized water. Upon UV
illumination, AgCl particles are gradually surrounded by silica particles (b and c). Around each AgCl particle an exclusion zone is seen, which
disappears when the UV is turned off. The disappearance of exclusion zones is seen in (d). Times in second are indicated in the upper left corners of
the images while the status of UV illumination is mentioned in the bottom left.52 Figure reproduced from ref 52 with permission from John Wiley
and Sons.

Figure 6. Transition between collective behaviors. (a) Oscillatory attach-release interactions between active silver chloride particles and nearby
passive silica spheres due to competing redox reactions;54 (b) silver orthophosphate particles disperse and cluster reversibly with addition and
removal of ammonia; (c) The transition from dispersion to clustering in (b) can be halted by UV, and the two different responses of the particles
under two orthogonal inputs enable the design of the universal “NOR” logic gate.55 Figures reproduced from refs 54 and 55 with permission from
the American Chemical Society.

Figure 7. Catalytic micromotors propelled by asymmetric generation and release of bubbles, demonstrating model applications such as (A) water
purification60 and (B) drug delivery.57 Figures reproduced from refs 60 and 57, respectively, with permission from the American Chemical Society.

Figure 8. Diffusion of (A) urease67 and (B) catalase68 increased as a function of increased substrate concentrations (urea and H2O2 respectively).
(* indicates a significance value of p < 0.05). (C) Enzyme-functionalized microparticles behave as hybrid autonomous motors in substrate solution.78
Figures adapted from refs 67, 68, and 78, respectively, with permission from the American Chemical Society.

nonbiological applications such as cargo delivery57 and water

purification60 (Figure 7). However, their use in living systems
■ SELF-POWERED MOLECULAR MOTORS
Along with the development of all-inorganic and hybrid motile
can be limited because of harmful effects of bubbles. systems, a major incentive has been to design biocompatible
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Figure 9. (A) Schematic of enzyme chemotaxis in Y-shaped microfluidic channel. In the presence of an imposed substrate concentration gradient,
active enzymes collectively move toward areas of higher substrate concentrations.68,69 (B) Chemotactic separation of active enzymes from their
inactive forms in the presence of imposed substrate concentration gradient.89 Figures adapted from refs 68 and 88, respectively, with permission from
the American Chemical Society.
active systems powered by biological fuels. Molecules of active
enzymes, which catalyze various biomolecular reactions with
extraordinary efficiency and specificity, offer excellent model
systems to develop smart molecular motors.65 In a series of
experiments, we demonstrated that active enzymes, while turn-
ing over substrates, generate enough mechanical force to
enhance their own diffusion in solution (Figure 8(A,B)).66−69
The diffusive movement of the enzymes increases with
increasing reaction rate, following Michaelis−Menten kinetics.
In order to account for the observed enhanced diffusion of
enzymes during substrate turnover, a number of theoretical
proposals have recently been put forward. Propulsion through
self-generated diffusiophoretic forces has been suggested for
molecules like urease, which generate ionic products during
reaction.70 Motility resulting from reaction-induced conforma-
tional changes in enzymes has also been proposed as a pos-
sibility.71 Bustamante et al. attributed the enhanced diffusion of
enzymes to the exothermicity of the chemical reactions
involved, where motion is induced via a local thermophoretic
effect.72 More recently, Golestanian estimated the magnitude of
diffusion enhancement originating from different possible
mechanisms and suggested that stochastic swimming due to
collective heating and conformational changes are more likely
to account for the experimentally measured diffusion enhance-
ment of the enzymes studied thus far.73 Using Langevin/
Brownian dynamics simulations, it was determined that a force
of ∼10 pN per turnover was sufficient to cause the enhance-
ment in diffusion of urease and catalase.66−68 These forces are
comparable to that produced by myosin, kinesin, and dynein
motors (approximately 10 pN),74−76 and within the range
necessary to activate integrins,77 biological adhesion molecules
responsible for mechanosensing by cells, making force produc-
tion by enzyme catalysis a potentially novel mechanobiology-
relevant event. Moreover, by tethering active enzymes to larger
micronscale particles, Sanchez et al. and we have independently
reported enhanced motion of enzyme-powered motors and
demonstrated that biocatalytic reactions may be used to power
large microscopic objects in solution (Figure 8(C)).78−80
The interesting behavior of self-powered systems at the
micro- and nanometer length scales encouraged us to extend
our investigation to even smaller active molecular systems.
There has been significant work on nanometer-scale synthetic
molecular systems, including rotors synthesized by the Feringa,81
nanocars designed by Tour,82 fluctuation driven transport
proposed by Astumian,83 and the shuttle systems discovered
by Leigh,84 Stoddart85 and others that move molecules along
chains. These systems are useful as switches, transport devices,
and even as subnanometer pumps. Again, taking a cue from the
7671
Perspective
biological systems, the ideal way to power motion in nanoscale
systems is though catalysis of chemical reactionsa critical
element missing from most work on synthetic molecular sys-
tems. Thus, it is important to investigate catalytically powered
motion that is compatible with this length scale. Using diffu-
sion NMR spectroscopy, we have examined the behavior of a
ruthenium-based Grubbs catalyst during its catalysis of the
ring-closing metathesis of diethyldiallylmalonate (DDM).86 As
with enzymes, the diffusion of the ∼6 Å radius organometallic
catalysts was found to increase with increasing reaction rate.
Additionally, the diffusion of the catalyst returned to the base
value upon either the addition of an inhibitor or the completion
of the reaction. Density functional theory (DFT) calculations
were performed to probe the effect of structural changes in the
ruthenium complex as a source of the increased diffusion. The
conclusion was that the difference between the largest and the
smallest form of the catalyst was not significant enough to
account for the increased catalyst diffusivity at most substrate
concentrations.
■ MOLECULAR CHEMOTAXIS
In the presence of an imposed substrate concentration gradient,
active enzymes collectively move toward areas of higher sub-
strate concentrations, displaying a novel example of molecular
chemotaxis (Figure 9A).68,69,87 The collective migration of
enzymes toward specific targets promises a variety of applica-
tions including sensing, targeted transport, and delivery. The
exact mechanism behind enzyme chemotaxis, however, remains
an open question. It may involve a Brownian ratchet mech-
anism arising from substrate-dependent enhanced diffusion.88
As with any nonequilibrium system, a continuous energy input
is required for the directional movement, in this case, to
maintain the substrate gradient. A second possible mechanism
involves the favorable enzyme−substrate interaction. If the
enzyme−substrate complex is more stable than the enzyme and
the substrate separately, then the enzyme will diffuse to regions
of higher substrate concentrations because of the resulting
lowering of the chemical potential for the system. Irrespective
of the mechanism, however, molecular chemotaxis is stochastic
in nature and is different from biological chemotaxis, which
requires organisms to have temporal memory of the concen-
tration gradient.48,49 The observation of chemotaxis suggests
that, for directed motion, it is not necessary for the active
molecule or particle to be asymmetric; one simply needs a
gradient in the substrate concentration.
The observed chemotactic behavior of single enzymes
suggests that for an enzyme that acts on the products of a
second, nearby enzymatic reaction might result in its collective
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movement toward the second enzyme; an example of collective
behavior at the molecular level. Thus, catalase was observed to
migrate toward glucose oxidase in the presence of glucose since
hydrogen peroxide is a product in the oxidation of glucose.68
Importantly, the novel observation of the universality of force
production by enzymes and the ability to harness theses forces
for directed molecular chemotaxis up a substrate concentration
gradient allows the rational design of new technologies for the
separation of active enzymes from a complex media. The
chemotactic separation of active biomolecules from a mixture
has been demonstrated to be sensitive enough to sort out
molecules possessing identical physical properties, which
cannot otherwise be accomplished using currently known
separation techniques (Figure 9(B)).89 In principle, the tech-
nique of chemotactic separation can also be used to separate
out other active catalysts from their less active or inactive
counterparts in the presence of their respective substrates and
should, therefore, find wide applicability. We also observed
controlled chemotactic propulsion of enzyme-functionalized
microscopic particles, a promising step toward developing
smart biocompatible payload carriers in complex physiological
environments.78
■
MOLECULAR PUMPS
Enzyme molecules, when immobilized on a surface, transfer the
mechanical energy derived from catalysis to the surrounding
fluid, resulting in directional fluid pumping. In effect, surface-
bound enzymes function as chemically powered machines
(Figure 10(A)).90−93 This was demonstrated using four differ-
ent enzymes as modelscatalase, urease, lipase and glucose
oxidase.90 Using e-beam evaporator, gold was patterned on a
polyethylene glycol (PEG)-coated glass surface. The patterned
surface was functionalized with a quaternary ammonium thiol,
which formed a self-assembled monolayer (SAM) on the Au
Figure 10. (A) Schematic showing formation of enzyme patterns on
PEG coated glass surface and fluid pumping by immobilized enzymes
in the presence of substrates.90−93 Figure adapted from ref 90 with
permission from the Nature Publishing Group. (B) Inhibitor assay
based on enzyme powered micropumps. The presence of inhibitor is
detected by monitoring changes in the fluid flow speed, the attenua-
tion of which is directly correlated with the inhibitor concentration.94
Figure reproduced from ref 94 with permission from John Wiley and
Sons.
7672
Perspective
surface. The negatively charged enzyme molecules bound
selectively to the SAM-functionalized gold patterned surface via
electrostatic assembly, resulting in an enzyme pattern on the
surface (Figure 10(A)). Alternatively, enzymes can also be
attached to the gold patch using biotin−streptavidin linkage
procedure.91,92 To monitor the fluid flow, sulfate-functionalized
polystyrene microspheres were used as tracers. Only in the
presence of the substrate, the tracer particles move away from
(urease) or toward (catalase, lipase and glucose oxidase) the
gold surface, indicating that the surrounding fluid is pumped
outward or inward, depending on the specific enzyme pump.
The pumping velocity increases with increasing substrate con-
centration and reaction rate. The fluid flow is driven by a
gradient in fluid density generated primarily through changes in
the solutal composition, rather than due to reaction exother-
micity.91,92 These rechargeable pumps can be triggered by the
presence of specific analytes, which enables the design of
enzyme-based smart devices capable of acting both as sensors
and pumps. Similar pumping can occur in gels incorporating
immobilized enzymes in the presence of substrates. For example,
gel-bound glucose oxidase pumps insulin out of gel particles
when glucose is added to the surrounding solution.90 This
research addressed one of the major drawbacks of many
synthetic micropumps that are nonbiocompatible and do not
interface well with the biological systems. An interesting
application of enzyme pumps is in the area of toxin detection
where the attenuation in pumping velocity can be related to the
concentration of toxins that inhibit the enzymatic reaction.94
Using this principle, sensors for toxic substances, like mercury,
cadmium, cyanide and azide, were designed using urease and
catalase-powered pumps, respectively, with limits of detection
well below the concentrations permitted by the Environmental
Protection Agency (EPA) (Figure 10(B)).
■ LONG RANGE EFFECTS OF MOLECULAR MOTOR
SYSTEMS
An important aspect of the dynamics of active catalyst particles
is their effect on their immediate surroundings. Studies con-
ducted with micron-scale organisms and catalytic particles show
that such active assemblies exert considerable influence over the
behavior of their surroundings.95−101 Diffusion of inert tracer
particles dispersed in a suspension of micron-scale swimmers is
dependent upon the total activity of a system; the higher the
total activity of the system, the greater the diffusion enhance-
ment of the tracers. Qualitatively, the enhancement was found
to be independent of swimming patterns and mechanisms,
signifying the generic role of dynamic coupling among the
swimmers and their surroundings, which facilitates the
distribution of momentum. A key question is whether these
effects are also observable at the very low Reynolds number
regime (i.e., at the molecular scale). A recent theory predicts
that the advection effects induced by active molecular catalysts
should also result in significant enhancement of diffusion of
passive molecules present in solution.102 Accordingly, we mea-
sured the diffusion of molecular tracers, benzene and tetra-
methylsilane (TMS), in a solution of Grubbs catalyst using
diffusion NMR spectroscopy.103 Interestingly, the diffusion of
these inert molecules also increased with increasing reaction
rate and returned to the respective base values upon the com-
pletion of the reaction. The experimental observations demon-
strate transfer of momentum from the active catalyst molecules
to the surrounding medium, the nature of which is surpris-
ingly similar to the behavior of microscopic active swimmers.
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J. Am. Chem. Soc. 2017, 139, 7666−7676
Journal of the American Chemical Society
Note that the enthalpy change for the ring-closing metathesis
of DDM is approximately +8 kcal/mol (endothermic)86 and
therefore cannot contribute to the observed enhanced diffusion
of the tracers. The most plausible mechanism involves reaction-
generated advection caused by catalyst molecules “stirring” the
solution, which is of great importance especially in intracellular
mechanics.104−109
Energy transduction by enzymes at the single molecule and
collective level opens up a new area in molecular biophysics.
Enzymes, in addition to their primary function as catalysts for
biochemical reactions, may have secondary functions as
mediators of dynamic interaction pathways. In addition, the
possibility of enhanced diffusive transport of molecules by
controlled “stirring” in physiological environment has impor-
tant scientific and technological relevance. The phenomenon
could provide new insights into the dynamics of cytoplasmic
glass-gel transitions and enhanced mixing in bacterial cells,
observed during various metabolic transformations.108 Finally,
momentum transfer from freely diffusing active catalysts
suggests the possibility that membrane-bound enzymes exert
force on cell-membranes, amplifying mechanically induced
signaling mechanisms.109
■ FANTASTIC VOYAGE
External field-driven motion leads to “lock-step” ensemble
behavior. To realize the dream of Asimov’s Fantastic Voyage,
the bots must be autonomous, harvesting energy from the
surroundings and reacting to information at the local level.110
Investigating systems involving molecules and micro/
nanoparticles is inherently challenging due to the stochastic
nature of particle dynamics, the limitations of experimental and
modeling techniques in characterizing nonequilibrium systems,
and need for multidisciplinary expertise.12
Despite the progress in the design of synthetic motors, they
cannot carry out complex tasks like their biological counter-
parts. More integrated functionalities and “division of labor” are
two key elements in future design of synthetic motors. The
ultimate objective of research in this area is to create a new
paradigm for the design of active functional materials and
systems by leveraging (a) precise molecular-level control of
materials to create functional building blocks, (b) mobility
resulting from biomimetic catalytic energy harvesting from the
local environment, (c) rapid and reversible assembly capabil-
ities provided by emergent self-assembly, (d) intelligence and
communication capabilities found in interacting microorgan-
isms, and (e) ability to perform specific tasks in response to
signals from each other and the environment.
From a fundamental standpoint, the scientific questions
that need to be addressed going forward are (a) What are the
possible mechanisms for momentum creation at the micro-
and nanometer length scales and their efficiencies in different
environments? (b) Are there optimal motor geometries for
sustaining directional motion? (c) How well can motion be
directed, preferentially by chemical gradients (i.e., chemotaxis)?
(d) What is the nature of interparticle interactions in driven
systems? (e) How do the ensemble dynamics of active materials
evolve in space-time? and (f) How to we effectively integrate
synthetic active molecular assemblies into the biological world?
The majority of the motors systems to date have not been
optimized. There has only been one study so far on efficiency
of artificial motor systems by Wang, Mallouk, and collabo-
rators.111 While the focus of nanomotors has been on the
development of new systems and how to make the motors
7673
Perspective
move faster or longer, little have been done on optimization of
the fuel or geometries. Such factors will significantly impact
motor speed, fluid drag, fuel consumptions and other factors.
In particular, motor systems need to be examined in greater
detail in terms of efficiency and compatibility with respect to
intended applications.112
The optimization of motor geometries is critically important.
Currently, the majority of motors have cylindrical, spherical or
screw-like structures. Such geometries may not be best suited
for their future intended applications. Motors for in vivo
applications have limitations on their shape and size. They must
be large enough for directional propulsion while being small
and flexible enough to squeeze through narrow capillaries. If the
interior of living cells is the intended target, the easiest way to
enter is through endocytosis which depends on the size and
shape of the motor.12
Thus, far, the focus of motor research has been on the
development of motors that move by one dominant propulsion
mechanism. However, incorporating orthogonal propulsion
mechanisms into a motor offers a greater degree of control.
Examples include magneto-acoustic hybrid nanomotors,113 as
well as motors that encompass opposing chemical and acoustic
propulsion.114 These are the first steps toward the fabrication of
true multifunctional motors by incorporating different
components for propulsion (multiple fuels), triggered collective
behavior (cargo capture/release, schooling/exclusion), and
targeting behavior (response to multiple stimuli).112
An important goal is to use motors as micro/nano machines
to accomplish what our current tools and instruments cannot.
While there have been proof-of-concept applications in recent
publications, we have yet to find a niche where motors are
indispensable or the technique of choice for a given application.
As such, the field is expected to evolve into one with more
emphasis on application-based systems. Perhaps the most
attractive application for catalytic motors, given the scenario
in Fantastic Voyage, is medicine. The immense advantage of
targeted motion over diffusion, allowing for the use of less
material, is a major incentive for the use of autonomous motors
for drug or cargo delivery.112,115−117 Biomedical applications of
motors, however, remain relatively unexplored, in part due to
the difficulty of motor navigation in vivo. Most studies on
motors are conducted in water with low ion content. This is in
contrast to biological fluids, which contain a multitude of ions
and other components. Blood, for example, is a non-Newtonian
viscous fluid that contains plasma, platelets, red and white
blood cells that may affect motors’ movement in many different
ways. Several additional hurdles remain before practical in vivo
applications of motors become a reality. First, the nano/
microtransporters must be derived from biocompatible mate-
rials with surfaces appropriately functionalized to promote cell
viability. Second, and equally important, is to design self-
powered nano/microbots that can use fuels that are biocom-
patible, preferably fuels present in the body. Ideally, the nano/
microtransporters will employ enzymes as catalysts and fuels
(e.g., glucose) present in living systems.118−120 Third, the
transporters need to be powerful enough to move against fluid
flows, such as blood flow. Furthermore, the energy transduction
mechanism should operate in high ionic medium present in
biological fluids. Finally, the most “futuristic” scenario involves
the design of populations of synthetic nano and micromotors
and pumps that have the ability to organize themselves intel-
ligently, based on signals from each other and from their
environment, to perform complex tasks. Particularly attractive
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J. Am. Chem. Soc. 2017, 139, 7666−7676
Journal of the American Chemical Society
are designs that allow coordinated movement of particles with
different functionalities that are not attached to each other,
making it easier to transport and deliver cargo at specific areas
as per requirements. The discovery of particle assemblies that
exhibit chemotaxis and predator−prey behavior is a step in this
direction. For many future applications, it will be important
to have motors that can independently carry out operations
such as sensing and reporting, with different populations of
interacting motors performing different tasks.
The observation that enzymes such as urease, catalase, lipase,
DNA polymerase, and others undergo powered movement and
pump fluids as they turn over their substrates amends the
paradigm that ATP-powered biomotors are a special class of
enzymes. This also clearly suggests that (a) single enzyme
molecules generate sufficient mechanical force through sub-
strate turnover to cause their own movement and that of the
surrounding particles and fluid and (b) the movement becomes
directional through the imposition of a gradient in substrate
concentration. Indeed, other than the presence of “tracks” that
provide directionality, there may not be a significant difference
between traditional motor proteins and free swimming
enzymes. In addition, it will be interesting to examine the
role of membrane-bound enzymes in cell membrane fluctua-
tions. The results described open up a new area of mech-
anobiology: intrinsic force generation by enzymes and their role
in biochemical regulation of cell function. These enzymes
can provide sufficient force for the stochastic motion of the
cytoplasm and the convective transport of fluid in cells.121
Further, they may be responsible for the observed glass to fluid
transition in active bacterial cells.108
The interaction between enzymes in living cells is an area of
active research. In many instances, enzymes that participate in
reaction cascades have been shown to assemble into meta-
bolons in response to the presence of the initial substrate to
facilitate substrate channeling.122−124 The mechanism for
metabolon formation, however, remains uncertain in many
cases. Metabolon formation through noncovalent interactions
has been suggested but rarely demonstrated.125,126 Our obser-
vation of preferential migration of enzymes up the substrate
gradient suggests that enzymes along a metabolic pathway in
which the product of one is the reactant for the next may
associate through a process of sequential, directed chemotactic
movement.
■
CONCLUSION
Chemically powered micro- and nanoscale motors offer immense
potential toward mimicking natural biomolecular systems
promising a myriad of novel technological innovations.127
However, the fabrication of tiny, efficient synthetic motors is
often associated with scientific and engineering challenges,
which need to be tackled with complementary theoretical and
experimental approaches. Since the discovery of the first
chemically powered system,128 many designs and propulsion
mechanisms for autonomous motors have been investigated
demonstrating their applications in transport, assembly, and
sensing. Freed of usual biological constraints, we now have the
unprecedented opportunity to probe the limits of self-organiza-
tion in these synthetic systems that operate far from equilib-
rium.129 Thus, it is possible to imagine a day when intelligent
machines navigate through the body and perform critical tasks,
realizing the functioning of Asimov’s Proteus.
7674
Perspective
■ AUTHOR INFORMATION
Corresponding Authors
*k.dey@iitgn.ac.in
*asen@psu.edu
ORCID
Ayusman Sen: 0000-0002-0556-9509
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We gratefully acknowledge Penn State MRSEC under NSF
grant DMR-1420620 and IIT, Gandhinagar for current financial
support and Anamika Dey for drawing some of the figures.
We thank the students and collaborators who have made
possible the results described in this perspective. A.S. also
thanks Dr. Suchismita Sen for insightful discussions.
■
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7676 DOI: 10.1021/jacs.7b02347

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