Driving Smart Molecular Systems by Artificial Molecular Machines

Biomolecular machines are widely present in nature, especially in complex living organisms, and are involved in important biological processes. Inspired by nature and increasingly mature synthetic technologies, a series of artificial molecular machines (AMMs) that exhibit similar processes and functions as biomolecular counterparts have been developed, and to date, some dramatic achievements have been obtained. Herein, the use of AMMs in smart systems and materials with controllable regulations and interesting functions are summarized, presenting the specific micro‐ to macroscale applications in solid surface modification, transmembrane transport, smart catalysts, liquid crystals, artificial molecular muscles, and stimuli‐responsive polymers. The challenges of developing novel complex AMMs with intelligent functions are discussed, and some potential solutions are proposed.


Introduction
Biomolecular machines play important roles in ensuring the operation of significant biological processes, such as DNA replication, protein synthesis, and transmembrane transport. [1][2][3][4] For example, adenosine triphosphate (ATP) synthase, a typical biomolecular motor found in living cells, undergoes unidirectional rotation driven by transmembrane cation flow to constantly synthesize ATP from adenosine diphosphate and phosphate. [5][6][7] Currently, inspired by these intriguing biological processes and the progress in synthetic organic chemistry, chemists aim to construct artificial molecular machines (AMMs) with functions similar to those of their biomolecular counterparts.

Microscale Applications
Molecular machines have been widely studied because of their ability to undergo controllable motion in response to external stimuli (e.g., light, electric, magnetic, chemical), and are figuratively denoted as "Hercules" in a microworld. [82][83][84][85][86][87] Several biomimetic AMMs have been designed and fabricated to work at the microscale, with this section focusing on three specific fields, namely, solid surface modification, transmembrane transport, and smart catalysts, in a detailed manner.

Solid Surface Modification
Molecules in solution tend to adopt a random orientation, which brings the net effect of the brought motion to zero. To overcome this problem and extend the application scope of molecular machines, one should establish proper carriers and optimize their working environment. In biological systems, ATP synthase and bacterial flagella are immobilized on the cell membrane to ensure stable operation and energy transfer, which has inspired researchers to mount AMMs on solid surfaces to improve performance. [46,[88][89][90][91][92][93] In 2003, Sauvage and coworkers [94] constructed copper [3]rotaxanes with a disulfide bridge in the molecule center, using the Cu(I) template effect and oxidative coupling to afford semirotaxanes and mounting them on a gold surface. Stoddart and coworkers [90] designed a nanomechanical device containing an array of microcantilever beams coated with a selfassembled monolayer (SAM) of bistable [3]rotaxanes. The interactions between cyclobis(paraquat-p-phenylene) 4þ macrocycle and two different recognition sites (tetrathiafulvalene and naphthalene units) could be manipulated via the addition of redox reagents to induce cyclic contraction/extension of the inter-ring distance in the bistable [3]rotaxane system, which was further converted into reversible bending of the nanomechanical device. These results represent the earliest attempt to construct a solid surface modification system, providing important guidance for later research.
Molecular motors can undergo directional motion in response to external stimuli. However, as the random orientation of these molecules may adversely affect organized motions, the mounting of molecular motors on proper carriers is essential to ensure ordered rotation. In 2005, Feringa and coworkers [95] connected molecular motors to a gold surface via thiol-functionalized "legs," using NMR, UV-vis, and circular dichroism studies to confirm that these motors can undergo photo/thermal isomerization and unidirectional 360 rotation. Subsequently, molecular motors were successfully grafted onto other carriers such as quartz and silicon using different surface chemistry approaches. [96,97] The weakness of these systems lies in surface overcrowding with immobilized motors, which inhibits their successful rotation because of steric hindrance. To mitigate this problem and accomplish controllable functions, Feringa and coworkers [76] designed fluorinated light-driven molecular motors and immobilized them on a gold film via tripodal stators in an altitudinal orientation relative to the surface, showing that the rigid phenylacetylenebased tripod provides sufficient space to ensure normal motor rotation ( Figure 2). In the initial state, stable-cis 1 SAM and stabletrans 1 SAM exhibit water contact angles of about 60 and 82 , respectively. Irradiation with UV light (365 nm) results in photoisomerization to afford unstable isomers, and the water contact angles change to 76 and 68 , respectively, as a result of hydrophobic perfluorobutyl group exposure/nonexposure. The aforementioned authors first used a light-driven molecular motor to control the surface wettability of a monolayer, and the unique tripodal design paves the way to the modification of functionalized molecular machines on solid surfaces.
Recently, Feringa and coworkers [98,99] designed a hostguest inclusion complex system comprising a light-driven molecular motor and tris(o-phenylene)cyclotriphosphazene (TPP). In this system, the long shafts modified on the rotors provide recognition sites for host-guest interactions with disc-shaped TPP crystals, leading to the coverage of their large facets with regular 2D trigonal arrays ( Figure 3). NMR and UV-vis analyses demonstrated that the molecular motors in this complex system undergo photo-and thermal isomerization processes similar to those observed in solution. Thus, it was concluded that molecular motors can overcome the surface confinement effect of crystals and undergo normal unidirectional rotation, which provides an instructive strategy to realize an ordered array and synergetic rotation of molecular motors on a 2D surface.

Transmembrane Transport
Bilayer membranes divide the living body into independent systems and ensure the normal operation of (sub)cellular structures, while some discrete entities self-assembling within a membrane may increase organism complexity. [100,101] Biomolecular machines are involved in various life processes, providing continuous transmembrane transport (e.g., energy transfer, mass transfer, and ion transfer) for useful work. Inspired by these biomolecular machines, researchers have fabricated diverse AMMs with similar functions. [102][103][104][105] In 2005, Feringa and coworkers [106] designed a light-responsive channel based on a spiropyran switch-modified MscL protein, showing that upon irradiation with UV light (366 nm), the photosensitive switch undergoes a structural transformation from a neutral spiropyran form to a charged zwitterionic merocyanine form, which results in channel opening and thus allows solutes to be transported across the membrane. Importantly, visible light (>460 nm) irradiation of the open channel results in the reverse (zwitterionic-to-neutral) transformation and, hence, in complete channel closure. The successful construction of this switchable transport system is a vital step to the practical functions of AMMs in biological systems and may therefore provide a new strategy of building artificial transmembrane transport systems. Jiang and coworkers developed a series of light-responsive nanoscale delivery systems based on azobenzene switches, [107,108] as exemplified by a selective ATP transmembrane transport system prepared by immobilizing azo-DNA onto the surface of conical polyimide (PI) nanochannels. [109] In this system, the PI nanochannels act as templates, while the azobenzene switch renders the system light-responsive. Irradiation with visible light (450 nm) favors the planar trans-state of azobenzene and, hence, the formation of a hairpin structure through stacking with adjacent base pairs. Importantly, this hairpin structure can be further stabilized by capturing two ATP molecules. Upon exposure to UV light (365 nm), the azobenzene switch undergoes photoisomerization into the cis-structure, which induces the collapse of the hairpin structure due to the unfavorable steric hindrance and thus results in ATP release ( Figure 4a). Remarkably, the above azo-DNA can be switched between folded and unfolded states by alternating irradiation with UV and visible light to realize the concomitant capture  [76] Copyright 2014, American Chemical Society. Middle left: Reproduced with permission. [77] Copyright 2018, American Chemical Society. Bottom left: Reproduced with permission. [78] Copyright 2019, Wiley-VCH. Upper right: Reproduced with permission. [79] Copyright 2014, Springer Nature. Middle right: Reproduced with permission. [80] Copyright 2016, Springer Nature. Bottom right: Reproduced with permission. [81] Copyright 2017, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com and release of ATP molecules and their transport across the membrane (Figure 4b). Similarly, Jiang and coworkers [110] developed a bioinspired system for the selective transport of β-cyclodextrins (β-CDs) across the membrane, relying on transformations between the transand cis-structures of azobenzene derivatives grafted onto PI membranes. In their trans-state, the azobenzene units engage in strong hydrophobic supramolecular interactions with β-CD to form inclusion complexes, while cis-isomer formation upon irradiation with UV light results in the dissociation of these complexes because of increased steric hindrance (Figure 4c). Upon simultaneous illumination with UV and visible light, the azo groups undergo persistent trans-cis conformation changes to result in the continuous trapping/release of β-CD molecules. This continuous rotation-inversion acts as molecular-level stirring to expel β-CD molecules from the nanochannels and thus complete transmembrane transport ( Figure 4d). The aforementioned bionic artificial molecular systems well simulate transmembrane transport processes to deepen our understanding of the biological machinery and thus have promising applications in the fields of drug separation and cancer therapy.
In living organisms, ions participate in various life processes and therefore need to be effectively transported across membranes. [111][112][113] According to driving forces, this transport can be classified into passive or active. Passive transport exploits the concentration gradient (high-low), whereas active transport acts in the reverse direction (low-high) and is facilitated by ion transporters, as exemplified by ATP hydrolysis and bimolecular machines. Inspired by these transport processes and their potential therapeutic applications, researchers constructed various artificial transmembrane ion transport systems with control possibility to mimic biological transport processes and functions. [114][115][116][117][118][119][120][121][122] Qu and coworkers [77] constructed a [2]rotaxanebased molecular shuttle for the transmembrane transport of potassium ions. In this shuttle, the ring component (CE) of [2]rotaxane comprises a dibenzo- [24]crown-8 (DB24C8) ring that can slide across the symmetric axle (T3) and a tethered smaller benzo- [18]crown-6 (B18C6) ring as a potassium ion receptor. T3 comprises two secondary ammonium units [(benzylalkylammonium hexafluorophosphate (BAA)] and a triazolium unit [N-methyltriazolium hexafluorophosphate (MTA)] that act as Figure 2. Schematic representation of the molecular motor immobilized on a gold surface and the related controllable wettability transformation of the monolayer. Reproduced with permission. [76] Copyright 2014, American Chemical Society.
www.advancedsciencenews.com www.advintellsyst.com DB24C8 recognition sites. Furthermore, the hydrophobic alkyl chains and hydrophilic stoppers endow the system with good biocompatibility (Figure 5a). The fabricated shuttle was incorporated into a bilayer to simulate ion transmembrane transport. During the transport process, the DB24C8 ring combines with the BAA recognition site and undergoes cyclic shuttling across the axle along with the back-and-forth movement of the potassium receptor B18C6, which results in the passive transmembrane transport of potassium ions driven by their concentration gradient. Remarkably, the MTA site in the center of the axle greatly reduces the shuttling energy barrier and increases transport speed. The aforementioned study largely simulates ion transmembrane transport in biological systems and extends the range of AMM work environments. The most important feature of molecular motors is their ability to undergo unidirectional motion and continuously perform work, which allows for applications in biological systems with physical processes. Tour and coworkers [123] innovatively exploited the rotation of molecular motors to open cell membranes ( Figure 5b). The motors were grafted onto a lipid bilayer by physical adsorption and irradiated with UV light to induce their continuous rotation. The resulting mechanical force allowed these motors to drill through the lipid bilayers and thus enabled the transport of molecular species across the membrane. Complementary experiments indicated that the sizes of groups modified on the stator influence the drilling process, with larger modified groups resulting in slower drilling speeds because of increased steric hindrance (Figure 5c). Theoretical calculations reveal that the mechanical force generated by the rotation of molecular motors can reach 540 mN m À1 , greatly exceeding the rupture stress of most bilipid membranes (1-30 mN m À1 ) and further evidencing the drilling process. Furthermore, the authors confirmed that this system can be used to target specific cells by modifying long peptide sequences. Thus, this work realizes the rotation of molecular motors in cells, providing a new direction for the design of nanodelivery systems and extending the application scope of specific recognition in biomedicine.

Smart Catalysts
Catalysts are commonly found in natural systems involving biological processes and mostly accelerate chemical processes with high reliability and efficiency. Therefore, the development of novel catalysts is important for their potential contributions in energy saving and environment protection. Molecular machines can respond to external stimuli and realize dynamic responsive behavior, which provides a new platform for the design of novel catalysts with controllable regulations. [70,[124][125][126] Feringa and coworkers [127] designed a molecular motorbased catalyst and used it to selectively synthesize different chiral products by regulating the catalytic moiety (Figure 6a). A dimethylaminopyridine (DMAP) Brønsted base (A) and a thiourea hydrogen-bond donor group (B) were grafted at the ends of the rotor and stator of the molecular motor, respectively, and the enantioselective Michael addition of 2-methoxythiophenol to cyclohexenone was used as a model reaction to investigate the catalytic performance of the system. In the initial state, the (P,P)-trans isomer was used as a catalyst to afford a racemic adduct with low efficiency (7% yield; Figure 6b,c), which was attributed to the unfavorable cooperation of DMAP and thiourea units due to the relatively large distance between them. However, upon photoisomerization, the (P,P)-trans isomer transformed into the (M,M)-cis isomer, which decreased the distance between the bifunctional moieties and induced a helical shape inversion of the whole molecule. These structural . Schematic representation of self-assembly between second-generation molecular motors and TPP crystals. Reproduced with permission. [98] Copyright 2017, American Chemical Society.
changes greatly increased catalytic activity (50% yield) and enantioselectivity (S-enantiomer/R-enantiomer ¼ 75/25; Figure 6b, d). Continuous thermal isomerization, which resulted in the conversion of the (M,M)-cis isomer to the (P,P)-cis isomer, did not affect the distance between the two functional groups, and catalytic activity was therefore sustained at a high level, but the concomitant helical shape inversion resulted in enantioselectivity inversion (S-enantiomer/R-enantiomer ¼ 23/77; Figure 6b,e). Notably, the configuration of the smart catalyst could be switched in situ from (P,P)-trans to (M,M)-cis by photoisomerization to markedly improve product yield (40%) and enantioselectivity (S-enantiomer/R-enantiomer ¼ 74/26). Thus, the aforementioned work paves the way to the application of AMMs in catalysis. Since then, several other molecular motor-based organocatalytic systems have been designed for different reactions. [128,129] Rotaxanes, an important type of MIM, can be precisely regulated under external stimuli, providing a valuable platform for the construction of smart catalytic systems. Generally, rotaxane-based smart catalysts are broadly classified into bistate unifunctional and bistate bifunctional systems. Most of these systems regulate the host macrocycle to slide across the axle to bind with different recognition sites and thus leave the catalytic groups exposed (on-state) or concealed (off-state). Over the past two decades, various controllably manipulatable rotaxane-based catalysts have been designed. [130][131][132][133] In 2012, Leigh and coworkers [134] designed a switchable organocatalyst comprising a host DB24C8 ring and two different binding sites (DBA and MTA), using the Michael addition of an aliphatic thiol to trans-cinnamaldehyde as a model reaction to study catalytic efficiency. In this system, the DB24C8 ring first combines with the DBA site to conceal the catalytic center (off state) and render the system catalytically inactive. Upon deprotonation of the DBA site, the DB24C8 ring prefers to reside at the MTA site, leaving the secondary amine catalytic center exposed and thus turning on catalytic activity. In addition, the above organocatalyst can be  [109] Copyright 2018, American Chemical Society. c) Schematic representation of supramolecular photoreactions between azo group and β-CD. d) Schematic representation of the bioinspired light-driven mass-transporting system. Reproduced with permission. [110] Copyright 2018, Wiley-VCH.
www.advancedsciencenews.com www.advintellsyst.com Figure 5. Schematic representation of a) transmembrane transport of potassium ions based on a [2]rotaxane molecular shuttle. Reproduced with permission. [77] Copyright 2018, American Chemical Society. b) Schematic representation of molecular motors for the disruption of lipid bilayers. c) Structures of molecular motors used to open cell membranes ("R" represents different modifications). Reproduced with permission. [123] Copyright 2017, Springer Nature. Figure 6. a) Schematic representation of a light-driven integrated unidirectional molecular motor and bifunctional organocatalyst. b) Reaction kinetics followed by measuring product formation by in situ 1 H NMR spectroscopy. c-e) Chiral high performance liquid chromatography traces of the reaction product using catalysts (P,P)-trans-6, (M,M)-cis-6, and (P,P)-cis-6, respectively. Reproduced with permission. [127] Copyright 2011, American Association for the Advancement of Science.
www.advancedsciencenews.com www.advintellsyst.com rendered inactive again by the addition of acids to protonate the newly formed amine species. Thus, this work successfully introduces rotaxane-based switchable catalysts and provides a basis for their further fabrication. [135][136][137][138] The dissipative systems of living organisms are involved in diverse biological processes, such as signal transduction and cell division. [139] Many artificial dissipative systems have been designed to mimic nature so far, but rarely with practical applications. Very recently, Leigh's group [78] developed a [2]rotaxane-based dissipative catalytic system (Figure 7) in which a thiourea group acts as an organocatalyst to promote nitrostyrene reduction. In the absence of an acid or base, the DB24C8 ring preferentially binds to thiourea to leave the catalytic center encapsulated and, hence, inactive. After the addition of trichloroacetic acid (1.1 equiv. to deprotonated shuttle), the secondary amine is protonated to induce the translocation of the crown ether to the newly formed ammonium group, exposing the thiourea moiety, and thus switching on catalytic activity. Protonation has to be continued for %9 h to reach a kinetic equilibrium along with the decarboxylic reaction of excess acid. Subsequently, the amount of the protonated shuttle decreases because of the formation of the nonprotonated shuttle, and finally, the initial thermal dynamic equilibrium is reestablished, with the only waste product being CHCl 3 . Notably, this full cycle can be completed at least seven times with pulsing fuel input. Thus, the aforementioned work successfully uses rotaxane-based dissipative catalysis with pulsing chemical fuel input to catalyze the reduction of nitrostyrene. The unique design requiring continuous energy input to preserve catalytic activity largely imitates the complex dissipative behaviors found in biological systems, providing an excellent opportunity to extend the application scope of AMMs to practical biological functions.

Macroscale Applications
An important AMM development direction is the mimicking of macroscopic objects to construct more complex machines and achieve synergistic operations of different elements for the fabrication of novel materials and devices with practical functions, which may revolutionize the biomedical industry and soft robotics. Up to now, various AMMs have been designed to perform controllable functions, and some dramatic breakthroughs have been realized. [46,68,140,141] This section focuses on the functional work completed by AMMs at the macroscale and summarizes the recent progress in the fields of liquid crystals, artificial molecular muscles, and stimuli-responsive polymers.

Liquid Crystals
In solution, molecules are generally present in unordered states because of Brownian motion. [142,143] However, organized ordered orientations are required for the molecules to perform synergistic and amplifying operations. Liquid crystals exhibit a highly ordered structure resulting from anisotropy in solution or molten state, which may provide a favorable work environment for molecular machines and therefore to achieve practical functions. Many liquid crystal-doped systems have been designed over the past few decades. [144][145][146][147][148][149][150][151][152] In 2006, Feringa et al. [153] embedded light-driven chiral molecular motors into a Figure 7. Schematic representation of operation mechanism of the dissipative catalytic system. Reproduced with permission. [78] Copyright 2019, Wiley-VCH.
www.advancedsciencenews.com www.advintellsyst.com cholesteric liquid crystal film, forcing this film to adopt the helicity of molecular motors. In response to external stimuli, these motors could undergo four isomerization steps along with helicity inversion in each step and thus induce the displacement/ rearrangement of liquid crystals. Helical shape changes in the full 360 cycle allowed one to rotate a glass rod exceeding the size of a single molecular motor 10 000-fold and thus successfully transform light energy into mechanical work. However, rotation changes could only be observed by optical microscopy, and the exploitation of nanostructure isomerization to induce macroscopic changes still remains challenging. Katsonis and coworkers [79] presented a helical-geometry liquid crystal polymer network with photoresponsive azobenzene derivatives and chiral dopants (Figure 8a,b), which was further made into chiral polymer springs. Optical microscopy confirmed that the ordered liquid crystal structures were preserved in the polymer network. Remarkably, the spiral ribbons could display different chiral shapes, depending on the direction in which they were cut (Figure 8c). Furthermore, the twisted ribbons could complete complex motions including winding, unwinding, and helical inversion in response to light stimuli (Figure 8d), which resulted from the increased disorder of the whole liquid crystal polymer network induced by the trans-to-cis configuration change of azobenzene switches. The initial state could be fully recovered by thermal relaxation under visible light, and the fact that reversible cycling could be conducted at least 10 times without distinct fatigue indicated excellent antifatigue properties. More intriguingly, these artificial ribbons could perform work against gravity by lifting objects with a much higher mass (Figure 8e). Thus, the aforementioned authors successfully converted nanoscale motions induced by configuration changes into macroscopic deformations, paving the way to the application of AMMs in life systems.
Oscillatory motions play important roles in life processes such as cell division control and nerve impulse/pattern formation regulation. [68] Inspired by these functions, chemists have tried to fabricate artificial materials capable of similar motions. In 2017, Broer and coworkers [154] developed a wave-like motion material by incorporating short-half-life azobenzene derivatives into a liquid crystal network, demonstrating the key role of fast cis-to-trans configuration changes in inducing polymer film deformation. Persistent irradiation of this film with constrained ends resulted in the generation of waves and their propagation along the long axis in a random direction, depending on whether the film orientation at the exposed side was planar or homeotropic. When the planar side was placed upward and illuminated with light, the waves propagated away from the light source, whereas the reverse was true when the homeotropic side was exposed to light. Theoretical modeling and numerical simulations were used to elucidate the mechanism of oscillatory behavior, indicating that wave generation and directional propagation were related to a negative feedback loop resulting from the integration of light-induced actuation, self-shadowing, and mechanical constraints. Furthermore, the polymer film was used to transport or uphill objects as well as to carry a plastic frame to undergo unidirectional movement. Thus, external energy input www.advancedsciencenews.com www.advintellsyst.com was innovatively transformed into practical macroscopic work, and the developed photoactuated polymer films are potentially applicable in the fields of photochemical energy harvesting, self-cleaning surfaces, and miniaturized transport. Katsonis and coworkers [155] developed a motile system relying on the handedness of light-driven molecular motors, demonstrating the helical motion trajectories of cholesteric liquid crystal droplets and simulating the motile behaviors of aquatic microorganisms and cells via bottom-up design (Figure 9a). Cholesteric liquid crystals were obtained by incorporation of chiral molecular motors in achiral nematic liquid crystals, and liquid crystal droplets were prepared by confining the photoresponsive cholesteric liquid crystals into spherical droplets composed of water and deuteroxide enriched in tetradecyltrimethylammonium bromide. In this system, deuteroxide was used to prevent the droplets from floating or sinking, while tetradecyltrimethylammonium bromide acted as a surfactant to ensure the helical motion of droplets. Remarkably, the produced chiral liquid crystal droplets were propelled along helical trajectories with a handedness opposite to that of these droplets (Figure 9b,c). The propulsion mechanism was explained by the initial formation of surfactant micelles that further solubilized small amounts of liquid crystals to create a surfactant gradient on the droplet surface, which formed surface tension and therefore led to droplet propulsion. More importantly, upon irradiation with intense light, the droplets significantly reoriented and underwent trajectory handedness inversion without obvious changes of radius and pitch (Figure 9d). Thus, the used bottom-up design allowed the molecular-scale handedness of molecular motors to be transformed into that of the liquid crystal helix, the spiral organization of droplets, and, eventually, into a helical trajectory to provide a new strategy of effectively regulating artificial molecular systems at the molecular level.
In addition to the self-propelled motion of liquid crystal droplets, the use of man-made actuators to realize liquid droplet motion holds great promise for their potential applications in biology, physics, or chemistry, which view microfluidic systems as important platforms. [156][157][158][159][160][161] Inspired by the lamellar structures of artery walls, Yu and coworkers [162] developed several photodeformable tubular microactuators (TMAs; Figure 10a) based on a liner liquid crystal polymer (LLCP), using external light to induce the asymmetric deformations of TMAs and thus control the motion of fluid slugs (Figure 10b). The used LLCP featured a long alkyl backbone and an azobenzene-functionalized side chain, with the long spacers providing enough free volume for the configurational transformations of azobenzene mesogens, while the azobenzene moieties acted as photoresponsive groups (Figure 10c). Ring-opening metathesis polymerization, used to ensure the mechanical robustness of LLCP and endow the polymer with other favorable properties (moderate elastic Figure 9. Schematic representations of a) the reorientation of spiral droplets in response to light-induced helix inversion; b) a chiral droplet trajectory; c) a helical trajectory of a left-handed droplet; d) a trajectory of a droplet containing Me-10 with helix inversion upon exposure to intense light. Reproduced with permission. [155] Copyright 2019, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com modulus, high toughness, high strength, and large elongation at break), was followed by solution processing to afford microactuators. Intriguingly, these microactuators could undergo obvious deformations upon irradiation by attenuated 470 nm light and propel liquid to move in either direction, depending on the direction of light intensity attenuation along TMAs. In contrast to previously reported liquid manipulation devices that could only achieve the regulation of specific liquids, the aforementioned microactuators were capable of propelling diverse liquids (train of slugs, emulsion, petrol, bovine serum albumin solution, etc.) and could even be used as micromixers to accelerate the dissolution of compounds. These fascinating liquid-handling abilities were attributed to deformation-induced capillary forces originating from the photocontrolled displacements and rearrangements of liquid crystal molecules (Figure 10d). Thus, the photocontrolled TMAs could be exploited to effectively handle liquid motion, having attractive prospects for applications in microdevice construction.

Artificial Molecular Muscles
In a living organism, muscle tissues rely on the conversion of chemical energy (ATP) into mechanical work, i.e., contraction and extension. Inspired by nature, chemists have developed a variety of artificial muscle systems and extended them to multiple dimensions (2D and 3D). [163][164][165][166] Generally, muscles can work at both micro-and macroscales, generating mechanical forces to regulate the distance between different objects. Several artificial molecular muscle systems have been constructed to fulfill similar functions. Qu et al. [167] designed and synthesized a daisy chain rotaxane-based nanoscale muscle-like molecular actuator and successfully used it to regulate the reversible changes of the distance between two gold nanoparticles under external stimuli (acid/base). This molecular actuator actually performs work at molecular level. However, to complete amplifying motions and macroscopic work, it is necessary to collect synchronized motions of molecular machines in space and time, while polymeric networks enjoy priority to realize these macroscopic changes.
To date, numerous polymeric network-based artificial muscle systems have been constructed to perform practical work. Harada and coworkers [80] fabricated a light-actuated muscle-like polymer by embedding a photoresponsive [c2]daisy chain comprising an α-cyclodextrin (α-CD) host and different binding sites (trans-azobenzene and secondary amine) into four-arm poly (ethyleneglycol) (tetraPEG) (Figure 11a). In this system, α-CD initially prefers to be located at the trans-azobenzene unit, Figure 10. a) Photographs of free-standing straight, serpentine, and helical TMAs. b) Light-induced motion of a silicone oil slug in a TMA; c) Molecular structure of LLCP. d) Schematic illustration of mesogen reorientation in the cross-sectional area of a TMA before and after light irradiation. Reproduced with permission. [162] Copyright 2016, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com and the formed hydrogel features an expanded shape. Upon exposure to UV light (365 nm), trans-azobenzene isomerizes into cis-azobenzene, which results in increased steric hindrance and poor interactions with α-CD. These structural changes drive the α-CD host macrocycles to slide across the long oxyalkyl chains and bind with the secondary amine recognition site to induce the macroscopic contraction of the hydrogel. The hydrogel initial shape and volume can be fully recovered upon exposure to visible light (430 nm), which induces the reverse (cis-to-trans) configuration change of azobenzene units (Figure 11b). Generally, the actuation mechanism of dry-type actuators is absolutely different from that of wet-type ones. As gel actuators are often driven by solvent absorption and desorption, some wet-type actuators may not perform work in the dry state. The aforementioned [c2]daisy chain-based xerogel, possessing fast response speed, well addressed the challenge. Upon irradiation with UV light (365 nm), the [c2]AzoCD 2 xerogel displayed an obvious bend toward the light source with a repose speed of 7.1 s À1 , which exceeded the corresponding hydrogel value more than 10 800-fold. In contrast to the hydrogel case, these shape changes could not be recovered by visible light (430 nm) irradiation because of the invalid regulations of the hydrophobic interaction and swelling pressure, while irradiation at the opposite side with 365 nm light allowed one to restore the deformations. Reproduced with permission. [80] Copyright 2016, Springer Nature. d) Schematic representation of the pH actuation of the [c2]daisy chain-based gel. Reproduced with permission. [168] Copyright 2017, American Chemical Society.
www.advancedsciencenews.com www.advintellsyst.com The good actuation ability of the xerogel was attributed to its flexible PEG chains, which allowed the sliding motions of [c2] AzoCD 2 units. More importantly, the xerogel was exploited as stimuli-responsive fingers to perform work with other components by lifting objects (Figure 11c). Thus, the aforementioned researchers developed two kinds of photoresponsive muscle-like actuators undergoing macroscopic changes upon exposure to external light and successfully used the dry-type actuator to perform work. Giuseppone and coworkers developed pH-responsive muscle-like polymers based on [c2]daisy chains. For example, an acid-base-switchable [c2]daisy-chain rotaxane with two 2,6-diacetylaminopyridine groups as stoppers was shown to undergo complementary hydrogen-bond interactions with the bis(uracil) linker and self-assemble into large bundles of fibers in a hierarchical manner. [169] In turn, these fibers could undergo in situ extension/contraction in response to the addition of an acid or base, which was attributed to the transduction of host rings between different recognition sites (secondary ammonium and triazolium units). These self-assembly morphologies as well as pH-induced actuation existed on the mesoscale and could only be observed with the help of microscopic instruments and nanotechnology. To realize macroscopic work, Giuseppone et al. [168] fabricated a novel muscle-like gel via a copper-catalyzed azide-alkyne cycloaddition reaction of pseudo-rotaxane bis-alkyne, bis-azide, and tris-azide components. In the initial state, the two host rings were located at the secondary ammonium recognition site, and the gel displayed an extended shape. Immersion into 1 M NaOH resulted in the deprotonation of secondary ammonium units and drove the rings toward the triazolium site, which further led to gel shrinkage. Notably, reprotonation of the [c2]daisy chains via treatment with aqueous ammonium hexafluorophosphate resulted in the reestablishment of the expanded state, and the contraction/expansion could be repeated for several cycles under external base/acid stimuli (Figure 11d). Thus, the [c2] daisy chain-based artificial molecular muscles successfully translated molecular-level synergistic variations into fully reversible macroscopic responses, which provided further insights into the amplification mechanism of dynamic controlled polymers.
In addition to linear molecular machine-based muscle systems, rotary molecular motors have also been used to construct artificial molecular muscle systems with similar functions. Feringa and coworkers [170] constructed a muscle-like material based on supramolecular interactions. Specifically, a light-driven molecular motor was modified with a hydrophobic chain on the rotor and a hydrophilic chain on the stator to form an amphiphilic motor monomer capable of self-assembly into nanofibers (Figure 12a). The nanofiber solution was transferred into a CaCl 2 Figure 12. a) Structural change of the amphiphilic motor due to the photoisomerization. b) Schematic representation of the self-assembly processes of the amphiphilic motor. c) Photoinduced bending of the supramolecular string in water. d) The muscle-like string performs work by lifting an object. Reproduced with permission. [170] Copyright 2018, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com solution, wherein the calcium ions and shear flow-based electrostatic screening further induced the unidirectional aggregation of nanofibers into aligned nanofiber bundles (Figure 12b). Photoactuation behavior was first investigated in an aqueous environment. Upon irradiation with UV light, the amphiphilic molecular motor underwent photoisomerization, which induced a helical shape inversion of the whole molecule to bend nanofiber bundles toward the light source ( Figure 12c). Importantly, this deformation could be fully restored by thermal isomerization and the accompanying opposite helix inversion. Furthermore, these aligned bundles also responded to external light stimuli in air, exhibiting a photoresponse similar to that observed in water. More intriguingly, the actuator performed mechanical work by lifting a 0.4 mg piece of paper (Figure 12d). To some extent, this muscle-like supramolecular self-assembly system largely mimics biological systems and extends the work environments of artificial molecular muscle to water and air, thus being potentially applicable in the fields of smart materials and soft robotics.
Although muscle extension and contraction have been widely simulated, the major challenge of developing artificial molecular muscles with practical functions is the realization of muscle-like mechanical adaptability, which may largely limit the further applications of these systems. Taking inspiration from the mutable collagenous tissues of biological systems, Katsonis and coworkers [171] developed actuating materials with complex mechanical adaptability by incorporating phase heterogeneity in a liquid crystal polymer network (Figure 13a). Exposure to UV light resulted in material stiffening or softening, depending on the molar ratio (R 0 ) between the free liquid crystal and the azobenzene-based network (Figure 13b). At a low content of free liquid crystals, light-induced softening was observed under both in situ and ex situ conditions, in line with the behaviors of previously reported homogeneous materials. [172][173][174] With increasing liquid crystal content, light-induced softening became progressively less pronounced, vanishing at R 0 % 3.9, and was then superseded by light-induced stiffening. These mechanical property changes were attributed to the light-controlled decrease of the miscibility of the free liquid crystals and the polymer network due to the trans-cis isomerization of azobenzene switches, which further generated elastocapillary forces to oppose interfacial area formation and thus suppress deformation, resulting in light-induced stiffening. The initial state and mechanical properties could be recovered by thermal relaxation. As the tunability of stiffness, including both softening and stiffening, represented an important prerequisite of muscle performance, the actuating Figure 13. a) Compositions of mechanically adaptive polymers and corresponding light-induced structural changes. b) Light-induced variation of the Young modulus (ΔE), for increasing swelling degrees (R 0 ). c) Response of a liquid crystal polymer spring to increasing pulling force. d) Muscle-like behavior of polymer springs (R 0 ¼ 4.7) upon illumination with UV and visible light. Reproduced with permission. [171] Copyright 2019, Springer Nature.
www.advancedsciencenews.com www.advintellsyst.com material (R 0 ¼ 4.7) was made into springs containing a small amount of a chiral dopant to simulate muscle-like work (Figure 13c). When such a spring was stretched under room-light conditions, a typical muscle-like nonlinear mechanical response was observed. Upon irradiation with UV light, the response curve shifted toward lower strains, and full recovery of the initial state was observed upon irradiation with visible light (Figure 13d). These stiffening/softening changes largely simulated muscle performance, and more importantly, the springs could perform work by lifting objects more than 10 times their weight. Figure 14. Molecular structures and operating principle of rotaxane-based mechanoluminophores. Reproduced with permission. [190] Copyright 2018, American Chemical Society. Figure 15. Molecular structure of the PAA and the polyrotaxane and a schematic representation of the operation of the PR-PAA binder to dissipate stress during repeated SiMP volume changes. Reproduced with permission. [191] Copyright 2017, American Association for the Advancement of Science.
www.advancedsciencenews.com www.advintellsyst.com Thus, this work encoded the mechanical properties of actuating materials using nanoscale molecular action and largely simulated muscle-like work, paving the way to the fabrication of smart materials and soft robotic systems capable of adapting to unpredictable surroundings.

Stimuli-Responsive Polymers
Polymers, representing an important platform for the combination of nanoscale chemistry and macroscopic objects, have been widely researched for potential applications in material science. [175][176][177][178][179][180][181][182][183] The introduction of stimuli-responsive molecular machine units into polymer systems to fabricate novel materials with advantageous properties such as self-healability, high stretchability, and recyclability has drawn increased attention, while the introduction of responsive units may also endow these systems with controllable regulation. [184][185][186][187][188][189] As rotaxanes possess distinct topology and can complete controllable motions at the molecular level, they can be exploited not only as building blocks to design complex AMMs but also as components of smart materials. Weder and coworkers [190] constructed a mechanochromic polymer based on a [2]rotaxane and successfully transformed force input into fluorescence output ( Figure 14). The [2]rotaxane acted as a force-responsive unit of the system, which comprised a crown ether macrocycle tethered with a fluorophore unit (4,7-bis(phenylethynyl)-2,1, 3-benzothiadiazole, BHT) and a 1,4,5,8-naphthalenetetracarboxylic diimide (NpI)-based axle. One hydroxyl group was reserved on both the cycle and dumbbell stopper for further integration with a polyurethane elastomer to form force-responsive polymers. In the nonstretched condition, the crown ether macrocycle was located at the NpI unit because of the strong donor-acceptor interaction between them, and the approach of NpI and BHT motifs caused fluorescence quenching to afford a nonluminous state. After stretching by an external force, the macrocycle slid away from the NpI recognition site to turn on polymer fluorescence. This deformation-induced turn-on of the luminous state could be reversed by the withdrawal of external force. Thus, the aforementioned design transduced macroscopic deformation into optical signals at the molecular level, representing a new  Compared with individual rotaxanes, polyrotaxanes possess a longer axle and numerous macrocycles, thus potentially exhibiting better biocompatibility, degradability, etc. In 2017, Kwon and coworkers [191] developed polyrotaxane-doped elastic binders and used them to prolong the lifespan of Si microparticle (SiMP) anodes ( Figure 15). The polyrotaxane comprised an amine-functionalized PEG chain, α-CD macrocycles, and dinitrobenzene stopper units. Elastic binders [polyrotaxane-polyacrylic acid (PR-PAA)] were obtained by covalently linking the polyrotaxane with polyacrylic acid (PAA) through esterification. The α-CD macrocycles were initially randomly oriented, while the PR-PAA was kept in a relaxed state. Upon lithiation, the SiMPs expanded, making the α-CD macrocycles slide across the PEG and PAA chains to reduce mechanical stress, which resulted in the coalescence of pulverized Si particles. Furthermore, the displaced rings could return from the high-energy state to the pristine state after delithiation. Remarkably, the electrode sustained its morphology after repeated lithiation/delithiation, which was largely ascribed to the polyrotaxane acting as moving pulleys to dissipate the tension generated on the polymer network. Thus, the aforementioned work introduced the usage of polyrotaxanes in lithiumion batteries to prolong the lifetime of SiMP anodes, paving the way to the application of AMMs in the energy field.
Apart from MIMs, molecular motors and molecular switches have also been used to construct stimuli-responsive polymers beyond the microscale. In 2015, Giuseppone and coworkers [192] reported a gel based on light-driven molecular motors that macroscopically contracted in response to external light irradiation by utilizing the unidirectional rotation of molecular motors. However, a disadvantage of this system is that the actuator can only rotate uniaxially and fails to complete reversible conversions. This design was subsequently optimized via the introduction of another dithienylethene-based modulator into the polymer networks to realize dual-wavelength controlled functions ( Figure 16a). [81] Upon exposure to UV light, the molecular motors continuously underwent unidirectional rotation with the modulators locked in the closed form to result in the macroscopic contraction of the gel. Conversely, upon irradiation with visible light, the molecular motors stopped rotating, while the modulators were transformed into the open form to liberate two freely rotating single bonds and thus unbraid the adjacent polymer chains. Therefore, the shrunken gel returned to the extended state (Figure 16b). The aforementioned work achieved dual-light control over a polymer network via the introduction of two different light-responsive units, providing a new strategy to overcome the unidirectionality limitation in some molecular machine-based systems. To some degree, this dual-control polymer also simulates muscle-like motions and can therefore possibly be applied to fabricate bio-like materials.

Conclusions
In 1959, Feynman [193] proposed the possibility of constructing micromachines at the nanoscale, but in view of the limitations of synthetic techniques and other factors, this prescient view has only been realized in recent decades. Until now, chemists have not only developed various AMMs using precise synthesis strategies, but have also tried to optimize the work environment of these machines to achieve spectacular functions and complete effective tasks. Some noticeable achievements of AMMs have been realized at both micro-and macroscales, as described in this Progress Report; however, the realization of further practical work still poses challenges. 1) Fabricating more complex AMMs. Currently, the study of AMMs is mostly based on individual molecules, which greatly limits further functionality. To improve the performance and extend the applications of AMMs, one should develop more complex systems with multifunctions, with the synergistic operations of different machine units providing a valuable platform. 2) The development of AMM-based solid devices. To perform practical work such as information storage and information transfer, it is necessary to transform AMMs into devices. Although liquid crystals provide strong support to fabricate molecular machine-based devices, solid devices exhibit higher potential in future applications, with solidification representing a fundamental step. So, it is crucial to research the integrated behaviors of AMMs in the solid state.
3) The study of the out-of-equilibrium processes of molecular machine-based systems. Out-of-equilibrium behaviors play an important role in living organisms, relating to energy dissipation and material exchange. Up to now, the characterization of molecular machines has mostly been performed in the still state, rarely involving out-of-equilibrium processes. Therefore, to extend the scope of molecular machine application in biological systems, it is vital to monitor out-of-equilibrium behaviors, which may require the assistance of precise or in situ instruments.
In conclusion, we envision that AMMs will bring us more pleasant surprises once the aforementioned challenges are solved in the future.