Stimuli‐Responsive Chemical Systems That Mimic Biological Dynamics

ABSTRACT

Living systems achieve adaptability, motion, and self‐regulation through chemical networks operating out of equilibrium. Reproducing these dynamics synthetically demands precise control over kinetics, thermodynamics, and molecular design to convert energy inputs into time‐programmed function. Recent advances in stimuli‐responsive and chemically powered systems show how life‐like behaviors such as oscillations, autonomous motion, adaptive responses, and compartmentalization can be encoded using fuel‐driven cycles and stimulus‐gated switches powered by chemical, photonic, or enzymatic inputs. This mini‐review highlights molecular assemblies that sustain transient states, molecular machines powered by specific chemical inputs, responsive materials that reconfigure in response to environmental triggers, nucleic acid‐based networks for sensing and regulation, and artificial cells that exhibit compartmentalization and signaling. Together, these developments bridge systems chemistry and biomimicry, expanding the chemical toolkit for engineering matter that can adapt and respond. Beyond mimicking biology, such systems deepen our understanding of the molecular foundations of living matter and open new routes to technology. Self‐powered systems, molecular motors, smart materials, and artificial cells now form a rapidly growing toolbox with the potential to impact drug discovery, biosensing, energy, food production, and materials science. The field's future lies in integrating multiple life‐essential functions into a single construct, ultimately enabling synthetic systems that replicate the complex network behaviors of living organisms and inspire next‐generation innovation.

Chemists are designing synthetic systems that mimic life's dynamic behaviors, such as motion, sensing, adaptation, and compartmentalization, by integrating reaction networks with stimuli like light, pH, and chemical fuels. This mini‐review surveys molecular machines, responsive materials, nucleic acid networks, and artificial cells, highlighting how chemical design drives the emergence of life‐like functions.

1. Introduction

Life's capacity to move, adapt, and self‐regulate arises from chemical networks that operate out of equilibrium in dissipative regimes that require continual energy input, which is transduced into chemical or mechanical work and then dissipated as heat or waste [1, 2]. Within such regimes, molecular recognition, catalytic cycles, energy transduction, and feedback loops coordinate to sustain biological function [3, 4]. Reproducing these dynamics synthetically is not mere biomimicry but a core chemical challenge: it requires deliberate control over kinetics, thermodynamics, and molecular design to convert energy inputs into time‐programmed function.

This review distinguishes two operational modes. Fuel‐driven (autonomous) systems consume fuel to generate transient states or dissipative steady states that persist only as long as energy flows. Stimulus‐gated (non‐autonomous) systems rely on external triggers such as light pulses, pH shifts, and redox toggles to modulate equilibria without net fuel turnover, thereby operating out of equilibrium. The former enables autonomy, sustained fluxes, and emergent behavior; the latter offers reversible, precise, low‐waste control.

Out‐of‐equilibrium systems are chemically displaced from equilibrium, whereas dissipative systems maintain this displacement by continuously consuming energy.

These modes highlight a broader principle: when molecular recognition is coupled to energy‐dissipating reaction networks, the resulting fluxes reshape the accessible state space and impose temporal direction absent at equilibrium. Under such conditions, design, kinetics, and feedback become inseparable, recognition directs energy flow, and dissipation determines which structures form, persist, or rearrange. This framework grounds the behavior of fuel‐driven motors, dissipative assemblies, nucleic‐acid circuits, adaptive materials, dynamic compartmentalization, and minimal artificial cells.

Within fuel‐driven systems, we focus on three major fueling strategies:

1. Chemical fueling, where high‐energy reagents (e.g., activated acids, anhydrides, alkylating agents) or gradients are consumed to bias kinetics and sustain out‐of‐equilibrium function, typically generating by‐products that must be managed;

2. Photonic fueling, where photons act as the energy source, often enabling remote, spatiotemporally precise, and in many cases waste‐free control (e.g., photoswitches, photocaged fuels);

3. Enzymatic fueling, where biocatalysts couple metabolic‐like cofactors (e.g., ATP) or specific catalytic cycles to materials and networks, imparting selectivity and the possibility of autonomous regulation.

Recent advances in stimuli‐responsive systems demonstrate that these principles encode oscillations, directional motion, adaptive responses, and compartmentalization in wholly synthetic matter [5, 6, 7, 8, 9, 10]. This review examines how chemical design converts energy inputs into life‐like functions across scales, from molecular machines to dynamic networks, nucleic‐acid systems, soft materials, and artificial cells. It outlines the key concepts of out‐of‐equilibrium operation, fueling mode, and autonomous versus non‐autonomous control that enable transient regulation and coordinated behavior. Together, these elements connect systems chemistry with biomimicry and provide practical rules for engineering emergent dynamics. Taking this into account, the examples have been grouped based on their parallels with biological dynamics.

2. Molecular Motors and Directionally Fueled Systems

Life's most fundamental processes rely on directionally fueled cycles that operate out‐of‐equilibrium. In biological contexts such as ATP hydrolysis in cytoskeletal motion or oxidative phosphorylation, chemical free energy is continuously dissipated to sustain directional work and self‐regulated dynamics. Translating this design principle into synthetic systems has inspired molecular machines that harvest energy to generate motion, transport cargo, or produce mechanical output. In what follows, we focus on chemically and light‐fueled motors and show, within each example, how kinetic asymmetry and dissipation produce directionality at the nanoscale, while making explicit the practical trade‐offs that still separate synthetic machines from their biological counterparts.

Even the simplest biological mechanisms proceed through fuel‐driven cycles in which a metabolic fuel biases a reaction network through high‐energy intermediates and rectifies thermal fluctuations into directed outcomes [11]. Synthetic motors mimic this logic by embedding ratchet mechanisms that convert unbiased Brownian motion into directed displacement. Crucially, direction emerges only when asymmetric kinetic pathways are traversed across a full reaction cycle and the energy invested is dissipated, preventing backtracking. Merely toggling an energy barrier (i.e., a stimulus‐gated step) is insufficient without cycle‐level bias.

A representative chemically fueled platform is the biaryl dicarboxylic‐acid rotary motor that cyclizes to an intramolecular anhydride upon reaction with a carbodiimide fuel (Figure 1) [12]. Subsequent hydrolysis with water returns the system to the diacid, and rotation about the aryl carbonyl bonds is permitted only in the anhydride state. Thus, the chemical work invested in anhydride formation selectively opens a Curtin–Hammett window, funneling interconverting conformers along a biased pathway; dissipation through hydrolysis prevents reversal and yields net unidirectional rotation over complete cycles. Variants with different stator–rotor pairs, including a naphthyl–phenyl system, achieve 360° rotation with ∼90% directional selectivity at each step [13], quantitatively demonstrating that the asymmetry is kinetic rather than a static thermodynamic bias. The same chemistry also exposes practical constraints that matter for real deployment: carbodiimide turnover produces urea waste that must be managed; reactive anhydrides impose narrow concentration windows to avoid intermolecular cross‐linking or aggregation; and fatigue can accumulate under continuous turnover unless fuel stoichiometry and scavengers are carefully engineered.

FIGURE 1.

Schematic representation of the dicarboxylic acid‐based molecular machine driven by asymmetric catalysts and fuels.

Analogue microscale‐fueled models with the ability to rotate have also been reported, such as an organopalladium‐based motor capable of a unidirectional rotary cycle using simple chemical fuels [14] and a system based on reversible lactone formation [15].

Pushing architectural complexity, Leigh, and coworkers reported a dual small‐molecule motor in which two pyrrole‐2‐carboxylic acid rotors are appended to a benzene‐2,5‐dicarboxylic acid stator (Figure 2) [16]. In each rotor–stator pair, anhydride formation and oriented hydrolysis promoted by a chiral catalyst induce rotation where the two rotors turn in opposite directions about the same axis. The anhydrides are formed under diisopropylcarbodiimide (DIC), an achiral fuel. Although the fuel is achiral, the promoter enforces stereodirectionality, cleanly localizing the kinetic asymmetry in the hydrolysis step rather than in fuel identity. The motor reaches ∼0.43 rpm initially (all fuel present) and sustains for ∼100 min at ∼0.24 rpm under continuous fueling with DIC. This clear separation between the role of the fuel and the role of the chiral promoter is mechanistically informative and suggests a path to asymmetric dual‐motor architectures with nonequivalent rotor environments or orthogonal gates.

FIGURE 2.

Schematic representation (A) and chemical mechanism (B) of the rotating functionality of a small molecule‐based dual molecular rotor. Both rotors work independently, and their rotation is fueled by the conversion of DIC into DIU and asymmetrically oriented by the employment of a chiral hydrolysis promoter.

But directional operation is not confined to rotation over a linear axle, and a notable example is a [2]catenane with two interlocked rings of different sizes (Figure 3). Fumaramide stations on the larger ring serve as binding sites for a smaller benzylic amide macrocycle. By installing and removing bulky blocking groups using the fuel 9‐fluorenylmethoxycarbonyl chloride (Fmoc‐Cl), the system erects dynamic barriers that rectify the macrocycle's motion around the track through mechanistically distinct attachment and detachment steps [17]. Because forward and reverse displacements traverse different chemical sub‐paths, the same fuel is dissipated asymmetrically, yielding net transport as a Brownian ratchet realized through covalent gating. Conceptually, this work introduces programmable checkpoints to promote or halt the flow of interlocked molecules; practically, it introduces new liabilities, from irreversible side reactions to by‐product accumulation, that must be contained to preserve track integrity over many cycles.

FIGURE 3.

9‐Fluorenylmethoxycarbonyl chloride‐fueled system yielding the clockwise movement of the macrocycle (blue) along the cyclic track (black).

A complementary example is a 21‐atom, two‐legged molecular walker that steps along a four‐footed track [18]. Each “foot” forms a covalent bond that is labile at a specific pH and locked at the other, enabling processive, sequential stepping. Motion is driven by disulfide exchange and trans‐hydrazonization, producing here a kinetic asymmetry characteristic of a Brownian ratchet. Like kinesin, a linear motor protein that powers essential cellular processes such as intracellular transport and division, the synthetic walker exhibits kinetic asymmetry and directional bias, functioning as a Brownian ratchet [19]. In both systems, free‐energy gradients bias stochastic motion to yield net displacement and gating suppresses slippage.

The catenane and walker exemplify how chemical fueling creates time‐asymmetric barriers that rectify motion via covalent gating and pH‐programmed lability. The same ratchet logic can be implemented with photonic gating, where photoswitches replace chemical blocking groups to modulate binding landscapes without adding chemical waste. In practice, chemical cycles provide baseline autonomy and force density, while light affords remote, orthogonal addressability for start/stop, bias, or spatially patterned transport on the same tracks. This complementarity motivates the integration of photonic overlays into chemically driven designs.

Under photonic control, Feringa, and collaborators embedded a light‐driven helical alkene switch in a liquid‐crystal film [20]. UV light (365 nm) induces photoisomerization; subsequent thermal helix inversion returns the chromophore to its initial helicity, completing a 360° rotation. Doping the film with the motor translates nanoscale torsion into macroscopic rotation, even turning objects ∼10³–10⁴ times larger than the molecule. This demonstrates energy transduction across scales, from photon absorption to molecular conformational work and, eventually, to mesoscopic torque. Photonic control uniquely offers remote addressability, wavelength selectivity, and clean reversibility with minimal chemical footprint; yet it also exposes limitations that must be engineered around: continuous irradiation is often required to maintain a state; optical penetration constrains sample thickness and geometry; and repeated cycling can induce photofatigue or photodamage. In practice, most light‐controlled motors are stimulus‐gated (non‐autonomous) unless a photosubstrate is actually consumed within the cycle. A natural evolution is orthogonal multi‐input design: let chemical cycles provide baseline autonomy, and use light for on‐demand spatiotemporal gating, thereby preserving precision while minimizing cumulative light dose. To make platforms truly comparable, reports should include energy‐in/actuation‐out metrics.

Bridging to native machinery, stimulus‐gated photoregulation of kinesin–microtubule motility has been demonstrated with azopeptide inhibitors appended to tail‐domain‐derived peptides (Figure 4) [21]. The azobenzene photoswitch enables reversible, light‐controlled inhibition of kinesin, allowing on‐demand toggling of microtubule gliding without reengineering the motor protein. This work is a practical blueprint for layering photonic control onto biologically active matter, even when the synthetic module itself is not fuel‐driven.

FIGURE 4.

The addition of photoresponsive azobenzene compounds to kinesin's tail domain inhibitory peptides translates into a phototunable activity resulting in the inhibition or activation of the movement of microtubules after visible or UV light irradiation, respectively. The irradiation with visible light (436 nm) enhances the isomerization to the trans‐isomer, while UV light promotes the formation of the cis‐isomer.

These case studies show that chemical and photonic fueling are most powerful when used together rather than in opposition. Chemical fuels give motors autonomy and force, but at the cost of by‐product buildup, tight concentration control, and eventual fatigue. Light, on the other hand, offers clean, precise, and orthogonal control but is limited by penetration depth and the need for continuous irradiation.

Nature already demonstrates how these modes can work in concert. In the retinal/rhodopsin cycle, light acts as a trigger while downstream chemical steps amplify and reset the signal; in photosynthesis, photon absorption generates electrochemical gradients that drive ATP synthase; bacteriorhodopsin similarly couples photonic inputs to proton pumping that fuels chemical work. In each case, light provides timing and selectivity, while chemistry delivers throughput and resilience.

This logic points directly to hybrid synthetic designs in which chemical cycles maintain dissipative operation and directional bias, and light is layered on top to start, stop, or reset the system. Incorporating load‐dependent fuel delivery or light‐activated rescue steps could prolong operational lifetimes and improve robustness. As the field moves forward, it will be important to report quantitative metrics such as work per fuel equivalent, rotation per photon, stall torque, and cycles to failure, so that different platforms can be compared on a level playing field and systematically improved.

3. Dynamic Chemical Systems

The molecular motors discussed above illustrate how directional function emerges when energy dissipation, kinetic asymmetry, and gating are embedded into a reaction cycle. Yet motors represent only one expression of this broader chemical logic. These same principles of energy flow, bias, and feedback don't stop at the molecular scale; they also govern how larger, more complex systems behave. As architectures expand from discrete rotors and walkers to dynamic networks capable of bond exchange, growth, or self‐organization, the focus naturally shifts from directional motion to collective regulation and adaptation. This motivates the transition to dynamic chemical systems, where reversible covalent chemistry, environmental inputs, and dissipative processes combine to generate replication, competition, and emergent behaviors that parallel biological network dynamics.

Biological function emerges from chemical networks that operate both at equilibrium and out‐of‐equilibrium. Viewing dynamic covalent systems through this lens is helpful because these networks can store, exchange, and dissipate chemical free energy in response to inputs such as pH, redox state, light, or added fuel. Reversible exchange through imine, disulfide, or hydrazone linkages allows transient reconfiguration and opens the door to feedback and regulation. In this way, molecular‐level chemistry connects to systems‐level behavior and offers a chemical basis for replication, competition, and adaptation.

A central work of this topic has been done by Otto and coworkers on an out‐of‐equilibrium replicator that couples reversible covalent exchange with supramolecular self‐assembly. The system starts with a peptide‐based dithiol building block in borate buffer, which undergoes thiol‐to‐disulfide exchange and slow oxidation by air, yielding a distribution of macrocycles. In the absence of agitation, the library rests near equilibrium and favors small nonassembling rings such as trimers and tetramers [22]. When mechanical energy is supplied by stirring or shaking, the distribution shifts toward larger macrocycles, especially hexamers and heptamers, which stack via beta‐sheet interactions and grow into micron‐long fibers. The use of seed with preformed fibers accelerates the formation of the matching ring size, providing strong evidence for autocatalysis. Also, the way agitation is applied acts as selection pressure (stirring enriches the heptamer, while shaking enriches the hexamer). The system exhibits hallmark traits of cooperative behavior, including sigmoidal growth kinetics and conformational transitions from random coils to ordered β‐sheet structures, as revealed by cryo‐TEM, CD, FTIR, and fluorescence spectroscopy (Figure 5). The key point is that replication requires continuous dissipation through mechanical input and through the oxidation flux that sustains the disulfide exchange network. Without this throughput, the system remains trapped in the small ring basin.

FIGURE 5.

Thiol‐based dynamic chemical systems reach divergent equilibrium states under different conditions. The introduction of shaking or stirring shifts the chemical conversion into trimeric and tetrameric peptide‐containing macrocycles toward hexamers and heptamers, respectively. Hexamers and heptamers can then polymerize into large‐scale fibres, self‐replicate, and rapidly seed new solutions of monomeric 1.

This platform also uncovers selection‐like dynamics under a simple ecological constraint. Serial dilution imposes resource limitation and periodic destruction and drives a mixed population of replicators toward a single dominant quasi‐species, as shown in Figure 6 [23]. Stable coexistence arises when different replicators draw on distinct monomer pools, which constitutes niche partitioning at the chemical level. These outcomes recapitulate competitive exclusion when resources overlap and resource partitioning when they do not, and they define the minimal chemical conditions required for selection‐like behavior. But the boundary with biology remains clear: the replicating fibers reproduce and compete but do not yet display the information fidelity, error correction, or genotype‐to‐phenotype coupling that underpin true biological evolution.

FIGURE 6.

Thiol‐based dynamic combinatorial libraries yield a certain population of products in dynamic equilibrium. Some of these products (5mers, 6mers, and 8mers) are preferentially composed of a specific ratio of the starting materials (1‐3). When populations of replicators are subject to out‐of‐equilibrium conditions of competition, differences in the composition of the building blocks of each replicator result in a competition for the system's resources. The selected populations are necessarily those with the highest dynamic kinetic stability, enabling them to compete better for resources and displace species occupying the same niche, thus resulting in their amplification in the final mixture.

Two conceptual lessons follow from this case study. First, energy input does not simply accelerate reactions; it reshapes the effective network by biasing kinetic pathways and by coupling assembly to growth and fragmentation. Second, environmental control is not a detail. The type and intensity of agitation determine fiber breakage rates and, therefore, the number of growth ends, thereby switching the system from a linear to an exponential regime.

Molecular cages also illustrate how dissipative chemistry can emulate the functions of biological chaperones [24].

Dynamic covalent cages provide a complementary route to dissipative function with a different mechanistic handle. Imine condensation between a cup‐shaped multialdehyde and a trivalent amine yields a [4+4] covalent cage that can capture and release guests in a way that depends on acid‐fueled input [25]. Here, acidity acts as a controllable energy source that regulates the assembly state and the binding landscape. As in the Hsp70 protein chaperone cycle, ATP hydrolysis controls the binding and release steps. In the synthetic cage, protonation controls bond formation and stability, imposing a directional sequence of capture and release as the environment is driven through an acid‐fueled cycle. In both cases, the key chemical logic is the same: a transient energetic bias sets the order of events, and dissipation prevents immediate reversal (Figure 7).

FIGURE 7.

Cyclic acid‐driven assembly of the [4+4] imine cage formed from a cup‐shaped multialdehyde and a trivalent amine. Fluctuations in acidity modulate the reversible condensation steps, biasing the system toward cage formation and subsequent guest exchange. The transient energetic input restructures the network of intermediates, steering the dynamic covalent landscape through a directional capture–release sequence

By applying these principles, dynamic covalent chemistry becomes a route to functions typically reserved for living matter. Replication arises when assembly and bond exchange are coupled so that existing structures accelerate the formation of the same kind of structure. Selection follows when fuel flow and environmental forcing set different growth and survival rates across competing assemblies. Adaptation emerges when network topology and building block choice permit shifts between dominant states as inputs change.

4. Stimuli‐Responsive Nucleic Acid Assemblies

The dynamic covalent networks (DCN) described above show how reversible bond exchange, environmental inputs, and dissipative fueling can generate replication, selection, and adaptive responses in fully synthetic settings. These systems demonstrate that life‐like behavior arises not from specific molecular identities but from the organization of reactions into energy‐dependent networks. Nucleic acids provide a natural next step in this progression. Their sequence‐encoded recognition, predictable thermodynamics, and modular reaction pathways make them uniquely suited for embedding the same principles, transient fueling, feedback, and network‐level control into programmable architectures. Thus, while the previous section focused on small‐molecule and supramolecular systems that emulate biological dynamics through covalent exchange, we now shift to DNA and RNA assemblies, where base‐pairing rules and strand‐exchange mechanisms enable precise temporal programming and open a versatile platform for stimuli‐responsive and dissipative operation.

Nucleic acids provide a programmable platform for constructing dynamic chemical systems. Beyond static nanostructures, DNA and RNA assemblies now access transient and out‐of‐equilibrium operation, where photonic fueling, chemical fueling, or enzymatic fueling controls lifetimes, amplitudes, and feedback. Such systems reproduce key biological motifs, offering a route to mimic regulation and adaptation in living matter.

4.1. Light‐Driven Dissipative Systems

Early demonstrations of light‐regulated DNA systems were pioneered in 2008 by Asanuma et al., who incorporated azobenzene moieties into oligonucleotides to control duplex stability through trans–cis photoisomerization [26]. Ultraviolet light at 365 nm produced the cis form and destabilized hybridization, lowering the melting temperature by about 15°C. Visible light restored the trans state and reestablished binding. The result was a reversible and noninvasive way to regulate assembly on demand.

Follow‐up studies by You and coworkers built DNA nanoswitches in which azobenzene moieties control structural transitions with high reversibility and retain performance over at least 20 cycles, as shown in Figure 8 [27]. This began to set expectations for cycling endurance and fatigue reporting.

FIGURE 8.

UV/Visible light‐induced transitions of the azobenzene‐based DNA nanoswitches resulting in reversible structural changes.

Also, Lu and colleagues extended the concept to strand displacement. In 2018, they showed that azobenzene insert molecules act as photoresponsive hinges within an aptamer [28]. Then, they designed a photo‐driven regenerative electrochemical biosensor based on a thrombin‐binding aptamer [29] and combined this azobenzene photoswitch technology with G‐quadruplex formation to achieve sensitive thrombin detection from 5pM to 5 nM concentration and demonstrated repeated regeneration under ultraviolet light without performance loss.

Škugor and collaborators introduced orthogonal addressability with a nonautonomous DNA walker that responds to distinct wavelengths [30]. The walker steps forward or backward in response to light input, and two‐step cycles were detected by fluorescence. This work showed that multiple photoactuators can be addressed independently within a single construct. It also clarified the boundary between stimulus‐gated and fuel‐driven behavior. Unless a photosubstrate is consumed, the device remains stimulus‐gated and nonautonomous, even after many cycles.

After establishing that light can regulate hybridization and reconfiguration at the nanometer scale, it can also organize collective behavior at the mesoscale of active matter. Hess and coworkers used azobenzene‐modified DNA linkers as programmable spacers between kinesin‐propelled microtubules [31]. DNA tethers served as selective crosslinkers, allowing filaments to organize into translational or circular swarms depending on rigidity. Ultraviolet and visible light reversibly switched the swarm assembly over many cycles. They went further by implementing DNA logic gates of the yes, and, and or type, and addressing distinct filament populations independently. This bridged molecular photoswitching with mesoscale collective behavior, showing that information processing by DNA can extend beyond the nanoscale.

The same photoregulated logic can be applied to continuous materials to convert conformational change into mechanical function. Willner and colleagues designed DNA polymer hydrogels with bipyridinium dithienylethene (DTE) crosslinkers [32]. Ultraviolet light closes the DTE ring and stiffens the network, while visible light reopens the ring and lowers stiffness by roughly an order of magnitude. A redox handle provided by dopamine oxidation and reduction adds an orthogonal input, and duplex or G‐quadruplex motifs introduce ionic responsiveness. These hydrogels undergo repeated stiffness cycling, recover predefined shapes, and self‐heal after cutting with substantial recovery of tensile strength. The approach combines photonic and chemical inputs into a single material to deliver adaptive mechanics without altering composition.

Taken together, the work above establishes azobenzene photoisomerization as a cornerstone of nucleic acid nanotechnology. Light‐driven operation provides precise spatial and temporal control and can be highly efficient. The tradeoffs are the need for sustained irradiation in many platforms and the constraints imposed by sample geometry and optical absorption.

4.2. Abiotic Chemically Fueled Dissipative Systems

Chemical fueling offers a complementary route to transient operation without enzymes. A versatile approach relies on activated carboxylic acids that decarboxylate, generating a transient pH profile that moves DNA devices into and out of functional states. Di Stefano and Ricci demonstrated this strategy with triplex‐forming nanoswitches and with receptors controlled by 2‐(4‐chlorophenyl)‐2‐cyanopropanoic acid (CPA) or nitroacetic acid (NAA) [33]. In the nanoswitch, fuel addition drove duplex‐to‐triplex folding and spontaneous reopening as pH recovered. Lifetimes were tuned from about 30 to more than 120 min by adjusting fuel concentration. In the receptor system, NAA triggered transient release and rebinding of a cargo strand with an amplitude from 10% to 90% set by the fuel dose, and both systems cycled multiple times, as shown in Figure 9.

FIGURE 9.

Fluorescence signal of a DNA triplex nanoswitch under dissipative operation. The Fuel addition triggers triplex formation, followed by autonomous return to the duplex state as the pH relaxes.

These results show that, even in the absence of enzymes, DNA architectures can operate dissipatively, consuming chemical energy to regulate binding and structure transiently. Compared to oscillatory pH systems based on biocatalytic or continuous fueling, the use of decarboxylating acids provides a modular and straightforward means to impose time‐programmed function. Such abiotic strategies thus broaden the fuel palette of nucleic acid nanotechnology, complementing photonic and enzymatic inputs with robust, tunable chemical cycles.

4.3. Enzyme‐Driven Cycles

After establishing that light and small‐molecule fuels can program transient behavior at the device scale, enzymatic fueling introduces catalytic selectivity and metabolic‐style cofactors, which open the door to autonomy and feedback. Ricci and colleagues reported clamp‐like DNA‐based receptors controlled by RNA fuels and RNase H [34]. The binding of an RNA fuel destabilized the triplex receptor–cargo complex, weakening its affinity from 7 nM to ∼4 µM. RNase H then selectively degraded the RNA, restoring the original binding affinity. This cycle enabled multiple rounds of transient cargo release and reloading, with up to seven load–release events demonstrated. The kinetics of cargo release were programmable by tuning either RNase H concentration, reducing half‐lives from 73 min at 5 U mL^{− 1} to 2 min at 50 U mL^{− 1}, or RNA fuel concentration, which prolonged half‐lives from 2 to 38 min across a 50–250 nM range. These results establish DNA receptors as robust dissipative machines tolerant of waste accumulation. Building on this, Gentile et al. introduced feedback‐regulated dissipative systems, in which communication between multiple DNA devices enabled hierarchical control of transient states [35]. Bucci et al. further validated these principles at the single‐molecule level using optical tweezers, confirming reversible receptor operation under enzymatic control and quantifying cycle‐to‐cycle kinetic drift [36].

Building on device‐level control, Walther moved to network‐level operation, using adenosine triphosphate as the fuel, and pushed the systems toward lifelike behavior. In 2019, ligation and restriction were coupled to create dynamic covalent DNA polymers that operate in dissipative steady states [37]. Lifetime scales with ATP level and enzyme ratios set chain length and exchange frequency. The materials self‐repair and relieve stress, linking mechanical response to fuel turnover. Light was then introduced as an orthogonal regulator through photocaged ATP and light‐responsive tiles [38]. This allowed wavelength‐selective activation, repeated refueling, and conversion of dormant tiles into active ones without cross‐talk when domains were designed orthogonally.

Extending from polymers to higher‐order assemblies, autonomous life cycles of DNA nanotubes (DNTs) were reported in 2021 using hierarchically concatenated reaction networks [39]. An upstream ligation‐and‐restriction module consumed ATP, and a downstream strand‐displacement cascade translated that consumption into the growth and decay of nanotubes. At this moment, two strategies were explored. In indirect activation, ATP‐fueled cascades released activator strands; in direct activation, the control module was placed on the assembling tiles, producing faster growth and higher yields per area but shorter average lengths. Orthogonal recognition domains enabled transient self‐sorting, allowing coexisting nanotube populations to assemble and degrade at different times, which echoes the temporal organization of cytoskeletal filaments.

In parallel, Willner showed that dissipative DNA networks can be driven enzymatically through lead dependent DNAzymes, which generate waste, or photochemically through azobenzene‐modified modules, which enable cyclic operation with minimal waste [40].

In 2023, constitutional dynamic networks (CDN) were coupled to dissipative modules to regulate biocatalytic cascades, including glucose oxidase with horseradish peroxidase and lactate dehydrogenase with nicotinamide adenine dinucleotide, as well as thrombin‐induced fibrin formation [41]. This moved the field from purely structural reconfiguration to the dynamic regulation of biochemical function. In 2025, enzyme and light control were merged with photocaged hairpins that release fuel strands on demand [42]. This strategy enabled the precise tuning of amplitude and rhythm in transient processes, combining the programmability of biocatalytic cascades with external control via light. Applications included light‐modulated fibrinogenesis and temporal regulation of the GOx/HRP cascade, illustrating how enzymatic and photonic fuels can be seamlessly integrated into sophisticated hybrid DNA architectures.

Looking at these systems collectively, these nucleic‐acid systems illustrate how sequence‐guided recognition, controlled fueling, and feedback can generate well‐timed, adaptable out‐of‐equilibrium behavior. But their effects are still felt mainly at the molecular and mesoscopic scales of strands, tiles, and nanotubes. The next step is to see how these same ideas, transient energy input, programmable network architecture, and dissipative control, can be carried into continuous soft‐matter systems whose behavior is visible as changes in stiffness, shape, or flow.

Smart materials offer this connection. By embedding molecular switches, catalytic cycles, and fuel‐driven reactions into polymer and hydrogel matrices, small chemical events can be amplified into macroscopic movements, oscillations, or self‐healing. In the next section, we therefore move from nucleic‐acid devices to responsive soft materials, and examine how the principles introduced in Sections 2 and 3 reappear as life‐like mechanical behaviors in gels and polymer networks.

5. Smart Materials

Smart materials are dynamic soft‐matter systems whose molecular architecture and macroscopic properties adapt reversibly to external or internal stimuli. These stimuli modulate molecular interactions and can induce oscillations, contractions, or self‐healing. Because responsiveness depends on continuous or intermittent energy input, these materials belong to the same thermodynamic framework as biological matter, where sustained dissipation maintains structure and function. The central challenge is to understand how molecular rearrangements propagate into collective transformations and to master this multiscale coupling so that dynamic chemistry yields material behaviors reminiscent of living systems. The ratchet logics of Section 2 and the reaction‐network feedback of Section 3 reappear here as oscillations, contraction, and transient morphogenesis encoded in polymer backbones and gel networks.

5.1. Contraction‐Responsive Materials

The first molecular demonstrations of contraction and extension came from Sauvage's rotaxane dimers, where metal exchange from Cu⁺ to Zn²⁺ produced about 25% length change [43]. Building on this principle, Stoddart introduced acid–base switchable [c₂]daisy chains, later assembled into polyrotaxanes that amplified motion cooperatively [43]. In parallel, Grubbs used ring‐closing metathesis to prepare stable daisy‐chain dimers that were incorporated into linear polymers, resulting in large, reversible dimensional shifts [44]. Together, these studies established the chemical logic of molecular muscles: mechanically interlocked motifs as contractile units, chemical or pH stimuli as triggers, and polymeric integration as a route to amplify motion. Although the absolute contractions remain modest compared to actomyosin, the design principle is the same: reversible work input and coupling between many molecular units generate collective movement.

Giuseppone and coworkers extended these ideas to muscle‐like materials. Metallosupramolecular polymerization of bistable daisy chains yielded long wormlike chains with degrees of polymerization above two thousand in which thousands of units contracted to give micrometer‐scale contour length changes [45]. More recently, hierarchical self‐assembly into fibers created a higher level of organization in which molecular contractions translated into coordinated morphological transitions of fiber bundles [46]. This hierarchy illustrates a central tenet of adaptive materials: direction and amplitude of contraction can be programmed chemically, and molecular‐scale asymmetry underpins emergent mechanical work at larger scales.

Parallel efforts have focused on isomerizable bonds as reversible triggers. Azobenzene photoisomerization has long enabled artificial muscles and responsive polymers, translating molecular‐scale motion into macroscopic deformation [47, 48]. Hydrazone Z/E interconversion similarly drives steric reorganization of helical polymer matrices and produces measurable thickness and color changes under alternating blue and ultraviolet light (Figure 10) [49]. These switches offer high spatiotemporal precision, repeatable cycling, and straightforward backbone integration, yielding adaptive materials with controllable optical and mechanical properties. Challenges remain in fatigue resistance and biocompatibility, yet the ability to operate under mild light control makes these systems promising for biomedical and soft‐robotic settings. At the concept level, they show how sustained photonic inputs can maintain adaptive mechanical states, an analogue of biological photocycles such as retinal isomerization. Compression and stretching driven by hydrazone isomerization reversibly tune color and thickness.

FIGURE 10.

Chemical mechanism and schematic depiction of the macroscopic changes of the photoswitchable isomerization of a hydrazone‐containing material undergoing color change upon exposure to light of different wavelengths.

5.2. Polymeric and Hydrogel Systems

Stimuli‐responsive polymers and hydrogels provide versatile scaffolds in which molecular switching, catalysis, and fuel turnover translate into macroscopic oscillations, actuation, and transient assembly. High water content and tunable viscoelasticity allow bond exchange and reaction networks embedded in the matrix to manifest as collective mechanical or rheological change.

In Yoshida's classical system, a poly(N‐isopropylacrylamide) network decorated with Ru(bpy)₃ catalysts couples to the Belousov–Zhabotinsky reaction so that periodic redox switching of the Ru centers drives rhythmic volume changes without external on–off input [50]. Substrate concentrations, temperature, or light set frequency and amplitude. Capsule self‐oscillating gels then embedded the same logic at the millimeter scale: alginate–Ca²⁺ cores with PNIPAAm‐co‐NAPMAm shells showed traveling chemical waves and synchronized, nonthermal flickering that depends strictly on the BZ reaction [51]. These examples function as abiotic metabolic networks in which a chemical pacemaker modulates polymer conformation through feedback.

Moving from oscillation to fuel‐programmed assembly, Boekhoven and colleagues designed minimal reaction networks that toggle supramolecular organization. Transient alkylation of carboxylates by dimethyl sulfate formed esters that triggered fibrous hydrogels, followed by spontaneous hydrolysis back to solution [52]. A complementary peptide strategy uses short amphiphiles that enter dissipative states upon continuous fueling; fibers persist only as long as fuel is consumed [53]. Lifetimes are tunable from hours to days by fuel load or pH. Rheology scales with fuel input, while microscopy reveals tip‐specific shrinkage, stochastic collapse, and simultaneous growth and decay reminiscent of microtubule instability.

Building on temporally structured matter, Hermans, and coworkers programmed autonomous Sol→Gel→Sol→Gel→Sol transitions in fibrillar hydrogels [54]. Thiazinane‐derived monomers, activated by chemical fuels, first formed imine‐crosslinked microsphere gels, then reconfigured into aldehyde‐bearing species that nucleated a second anisotropic fiber gel. A deactivating fuel restored the sol state (Figure 11). By tuning the input sequence and stoichiometry, lifetime and morphology of each state are predictably set. This mirrors biological resource management in which stress granules and cytoskeletal filaments appear only within defined energetic regimes.

FIGURE 11.

Sol→Gel→Sol→Gel→Sol fibrillar hydrogel transitions in a time‐programmed dynamic system. The letters around the cycle indicate the main species present at each Sol/Gel phase of the cycle.

The ambition to mimic cytoskeletal dynamics pushes further. Dogic and collaborators created microtubule‐based active matter powered by kinesin clusters that hydrolyze ATP to generate continuous work [55]. Networks showed internally generated flows, buckling, fracture, and recombination, and, at high connectivity, formed bundled active networks with turbulent‐like streaming. Confinement produced 2D active nematics with defect creation, annihilation, and self‐healing. In a fully synthetic analogue, van Esch reported carboxylate monomers activated by methyl iodide that assemble into transient tubular structures and disassemble upon hydrolysis [56]. Repeated fueling restarts polymerization, capturing energy‐dependent growth and shrinkage cycles. These studies show a common rule: energy flux dictates persistence and organization of filaments in both biological and synthetic contexts.

Beyond cytoskeletal mimicry, hydrogels have been engineered for biomedical functions. A β‐lactamase‐responsive hydrogel built from four‐arm PEG–thiol scaffolds cross‐linked by β‐lactam maleimide linkers releases antibiotics selectively when pathogen enzymes cleave the linker (Figure 12) [57]. Eelkema's dynamic covalent dextran hydrogels use lipoic acid side groups to form β‐dithiane carbonyl crosslinks under mild reduction, conferring shear‐thinning and self‐healing while protecting peptide antigens and enabling sustained release [58]. In both cases, out‐of‐equilibrium adaptability couples mechanical resilience with biochemical specificity, and the response is decided by enzymatic or redox context.

FIGURE 12.

A β‐lactamase‐responsive hydrogel for the selective release of the cargo in the presence of resistant β‐lactamase‐expressing bacteria.

Adaptive actuation is also achieved by coupling chemical or photothermal inputs. A bilayer design with a disulfide‐crosslinked top layer locks strain in a polyacrylamide underlayer; reduction by an autocatalytic thiol front releases the strain, changing shape [59]. Aida's anisotropic PNIPA/TiNS hydrogels combine lower critical solution temperature transitions near thirty‐two to thirty‐four degrees Celsius with plasmonic heating from gold nanostructures to achieve large elongations and peristaltic crawling; near‐infrared activation enables actuation through tissue phantoms within seconds (Figure 13) [60].

FIGURE 13.

A photoresponsive hydrogel actuator, composed of gold nanoparticles embedded in titanate nanosheets, exhibits rapid, reversible, and anisotropic photothermal deformation, enabling earthworm‐like peristaltic crawling with direction reversibility controlled by laser scanning.

Finally, more sophisticated chemistries encode feedback and adaptive mechanics directly into networks. Embedding allylic phosphonium salts in disulfide‐crosslinked hydrogels creates self‐amplifying thiol cascades in which thiol inputs liberate phosphines that reduce disulfides to generate further thiols, culminating in macroscopic gel degradation [61]. This gives ultrasensitive detection of thiolated analytes and damage‐triggered failure when mechanical scission initiates the cascade. Guan's metallopolymer networks use imidazole‐bearing polymers cross‐linked with cobalt, zinc, or copper to undergo dynamic ligand exchange and redistribute coordination nodes under stress [62]. Free imidazole chains facilitate bond reshuffling, enabling reversible stress relaxation and tunable transitions between fluid‐like and solid‐like behavior.

As this section shows, smart materials can turn molecular switches, fuel cycles, and reaction‐network feedback into visible, tangible behaviors, oscillation, contraction, self‐healing, and more. But even the most advanced gels and polymers still miss a key hallmark of living systems: the ability to organize chemistry in space and time within discrete, functional compartments. In biology, compartments allow chemical fluxes to be focused, buffered, and coordinated, so that reactions become selective, regulated, and ultimately autonomous. Moving from adaptive materials toward truly life‐like behavior, therefore, requires systems that do more than respond to stimuli; they must create and sustain microenvironments that concentrate components, modulate reactions, and maintain energy‐dependent states. This is where peptide‐based coacervates come in. These dynamic, selectively permeable droplets assemble, reorganize, and dissolve in response to chemical or enzymatic cues, providing the kind of mesoscale organization that smart materials alone cannot. In the next section, we examine how such peptide‐rich condensates act as dissipative compartments, localizing matter and energy, coordinating reaction networks, and offering a practical route toward protocell‐like behavior in synthetic systems.

6. Peptide‐Based Coacervates as Dynamic Compartments in Life‐Like Systems

Compartmentalization is a fundamental organizing principle in the transition from chemistry to biology. In life‐like systems, it does not merely involve spatial separation but rather the organization of matter, energy, and information flows to sustain dynamic states far from equilibrium [63, 64].

Compartments provide localized environments where reactions can be concentrated, coordinated, and regulated, enabling the emergence of autonomous and adaptive behavior. Peptide and polyelectrolyte‐based coacervates have recently emerged as versatile biomimetic models that reproduce many of these functions. They act as dynamic, stimulus‐responsive, energy‐coupled microenvironments, positioning them as experimental analogues of protocells or prebiotic reaction units [65].

Coacervates arise from liquid–liquid phase separation (LLPS) driven by electrostatic, hydrophobic, and cation‐π interactions between charged polymers or peptides [66]. This spontaneous organization leads to selective concentration of macromolecules, cofactors, and reactants, enhancing local reactivity and reducing kinetic barriers.

In peptide‐based systems, the amino acid composition, particularly aromatic and cationic residues, governs the stability, viscosity, and selectivity of the condensed phase [67]. (Figure 14). Incorporating specific motifs such as Arg–Trp or Tyr–Lys enables the design of condensates with tunable capture and release behaviors [68].Such selective enrichment provides the confined, reactive environments necessary for prebiotic catalysis and emergent metabolic organization.

FIGURE 14.

Schematic representation of the different types of coacervates formed according to the chemical nature of the peptide sequences used.

A hallmark of peptide coacervates is their tunable semipermeability. Their molecular composition allows selective exchange of molecules based on charge, size, and hydrophobicity. Moreover, coacervate assembly and stability can be regulated by external stimuli such as pH, redox potential, ionic strength, or chemical fuels [69].

Recent systems display reversible assembly and disassembly in response to enzymatic activity or fuel consumption [70, 71], thereby mimicking the homeostatic regulation of living cells. These compartments thus operate as nonequilibrium dynamic entities, maintaining a transient yet functional identity.

When internal reactions alter the composition or charge of coacervate components, feedback loops can arise that stabilize or destabilize the condensate, leading to homeostasis or oscillatory behavior. For instance, phosphorylation or protonation events can trigger droplet dissolution or reformation, providing chemical analogues of regulatory feedback observed in biological organelles [66].

Peptide coacervates also function as microreactors: local crowding, altered dielectric environments, and selective enrichment can accelerate or redirect reaction pathways [72]. Recent studies show that these droplets can enhance enzymatic catalysis or host autocatalytic networks, highlighting their potential as minimal metabolic units and platforms to study energy–reaction coupling in synthetic cells.

Advances in design have yielded multiphase or membrane‐shelled coacervates that feature internal gradients in composition, polarity, and viscosity. Such architectures introduce functional specialization, spatial separation of reactions, and selective exchange across internal interfaces. Together, these developments transform coacervates into complex compartmental modules analogous to organelles or protocells [73]. (Figure 15).

FIGURE 15.

Schematic phase diagram of complex coacervation at charge neutrality, showing binodal curves corresponding to increasing interaction strength, alongside an illustrative pathway for the emergence of multiphase droplets. The diagram highlights how progressive changes in interaction parameters guide phase separation and subsequently enable hierarchical organization into nested droplet morphologies.

Integrating peptide and polyelectrolyte coacervates into the broader framework of life‐like chemistry redefines the concept of compartmentalization. The current challenge lies in coupling multiple functions, such as catalysis, replication, and energy transduction, within dynamically assembled compartments that preserve identity while adapting to change. In this context, coacervates provide an experimental platform to explore how chemical systems may acquire the hallmarks of living matter.

Peptide‐based coacervates provide a natural link between biomimetic compartmentalization and the construction of artificial cells. Their dynamic, energy‐dependent behavior reproduces essential features of living systems, including selective permeability, and adaptive regulation. As membrane‐free protocell models, they offer a chemically versatile platform for coupling reactions and stimuli within confined spaces. Integrating such coacervates with lipid membranes, enzymatic networks, or genetic modules represents a promising route toward minimal artificial systems with life‐like functionality.

7. Artificial Cells

The peptide‐based coacervates discussed above demonstrate how simple chemical components can self‐organize into dynamic, selectively permeable, and energy‐responsive compartments that concentrate reactants and support rudimentary regulation. Yet, despite their remarkable ability to mimic aspects of intracellular organization, these condensates remain minimal and largely membrane‐free. A natural progression is therefore to explore how such chemically programmed microenvironments can be integrated into more architecturally complex constructs that more fully emulate cellular structure and function. Artificial cells provide this next level of organization. By combining compartmentalization with metabolism, information processing, and adaptive behavior, they extend the principles established in coacervate chemistry, such as selective enrichment, feedback, and out‐of‐equilibrium operation, into systems capable of coordinated, multistep functionality. In the following section, we examine how lipid vesicles, polymeric protocells, and hybrid soft‐matter constructs incorporate fueling, reaction networks, and spatial organization to recreate increasingly sophisticated life‐like behaviors, and how these advances build directly on the dissipative compartmentalization showcased in Section 6.

Artificial cells are a key frontier in biomimetic and systems chemistry because they reconstruct minimal life‐like functions within synthetic or hybrid architectures. Below, we organize recent progress according to three core chemical principles that define life‐like behavior: reaction networks, compartmentalization, and communication/signalling

7.1. Reaction Networks and Dissipative Chemical Control

One major line of research illustrates how artificial cells operate through energy‐driven reaction networks. Work by Bonfio and coworkers on primordial protocells shows that environmental cycles of assembly and disassembly reorganize internal components and support inheritance‐like behavior without transport machinery, revealing how primitive lipid bilayers could sustain protocellular reaction fluxes [74]. Complementing these models, Pérez‐Mercader and colleagues developed fully synthetic protocells in which reversible polymerization coupled to copper‐catalyzed click chemistry generates vesicles capable of adaptive morphological changes. These vesicles operate under continuous energy input, forming chemical feedback loops that sustain out‐of‐equilibrium dynamics reminiscent of metabolism and environmental responsiveness [75]. Recent synthetic biology efforts further advance energetic autonomy by demonstrating ATP production inside artificial cells, a critical step toward maintaining sustained reaction cycles [76].

Replication and protein synthesis are fundamental cellular functions, so reconstituting transcription and translation inside compartments is a central goal. Lipid vesicle systems can encapsulate the machinery for RNA and protein synthesis and autonomously produce biomolecules from DNA templates. Nutrient uptake from the surrounding medium maintains function and enables sustained transcription and translation. These platforms have been used to generate therapeutic proteins directly in tumor microenvironments, illustrating the potential of artificial cells for in situ biomanufacturing [77] (Figure 16). Artificial cells can also execute synthetic DNA programs. Bar‐Ziv and coworkers constructed silicon‐supported, cell‐free platforms where spatially confined DNA templates generate oscillatory protein expression, gradients, and feedback‐regulated patterning that mimic natural gene‐control circuits [78, 79, 80]. Precise surface patterning recreates biomimetic crowding and ensures that reaction networks operate with spatial and temporal fidelity.

FIGURE 16.

Lipid‐based vesicles containing cell‐free protein synthesis systems work as synthetic cells expressing (transcription + translation) the genes from a DNA template. The proteins synthesized can exhibit therapeutic activities, such as antitumorigenic effects against cancer cells in culture or even tumor tissue in mouse models.

7.2. Compartmentalization and Controlled Microenvironments

Compartmentalization is a defining principle of artificial cells, enabling selective confinement, regulation, and amplification of chemical reactions. Soft‐matter scaffolds such as polymersomes and lipid vesicles provide tunable platforms where reaction environments are isolated yet chemically programmable. For example, biodegradable polymersomal bioreactors loaded with enzymes perform compartmentalized catalysis and regulated molecular recognition; surface modification with cell‐penetrating peptides allows programmed interaction with living cells [81, 82]. (Figure 17)

FIGURE 17.

Catalase‐loaded PEG‐PCIgTMC‐based polymersomes as biocompatible antioxidant agents in human cells.

Lipid droplets similarly serve as model protocells. Kurokawa and coworkers engineered an artificial cytoskeleton of DNA nanostructures embedded within lipid membranes, increasing robustness to osmotic stress and illustrating how internal scaffolding can stabilize compartmental organization [83]. These systems demonstrate how compartmental geometry, permeability, and internal structuring determine diffusion, reaction rates, and overall functional behavior, chemical parameters that define life‐like operation.

7.3. Communication and Signaling Across Interfaces

A third essential function of artificial cells is communication, enabling them to respond to external cues or exchange information with other compartments. Mashima and collaborators developed synthetic cells that sense a defined chemical signal and respond by sequestering or releasing protein cargo. DNA barcodes direct cargo localization and support multiple, programmable cycles of uptake and triggered release, offering a chemically encoded communication interface [84].

Further illustrating chemically driven signalling, nanosensor membranes detect liposome fusion by tracking changes in enzyme activity. Thermoresponsive membrane receptors modulate L‐lactate dehydrogenase activity in the presence of NAD⁺ and copper ions, demonstrating how membrane‐bound molecular switches convert environmental inputs into functional biochemical outputs [85].

These examples show how signal detection, transduction, and response can be encoded in synthetic constructs using modular chemical interactions, an essential step toward interactive, autonomous artificial cells.

8. Summary and Outlook

Across the systems discussed in this review, from molecular motors and DCN to nucleic‐acid circuits, innovative materials, coacervates, and artificial cells, a common theme emerges: life‐like behavior arises when recognition processes are embedded within energy‐driven reaction networks capable of feedback, adaptation, and spatiotemporal control. The next advances in the field will depend less on inventing entirely new motifs and more on overcoming several concrete challenges that currently limit the robustness and integration of these systems.

A key issue is energy‐coupling efficiency. Many dissipative platforms require continuous irradiation, high fuel loads, or large excesses of cofactors, leading to energetic overheads far from biological standards. Designing architectures that maximize kinetic asymmetry, recycle fuels, or channel energy into productive pathways will be central for building sustainable, long‐lived systems. Closely tied to this is waste management: unlike living cells, few synthetic systems can neutralize or reorganize by‐products, which often accumulate and disrupt operation. Embedding waste‐processing modules or engineering fuel cycles with benign or reusable outputs would greatly expand operational lifetimes.

Another key frontier is the integration of multiple stimuli and feedback loops within single constructs. While most current systems respond to one dominant input, life‐like adaptability requires chemistries that combine photonic, chemical, redox, enzymatic, or mechanical cues in mutually compatible ways and route signals across scales. Achieving this demands tighter coupling between reaction networks and material mechanics, so that structural changes can regulate chemical flux, an analogue of how cytoskeletal tension modulates biochemical pathways in cells.

Compartmentalization also presents open challenges. Coacervates and vesicles now reproduce selective permeability and localized catalysis, yet the dynamic control of fusion, fission, internal gradients, and identity maintenance remains limited. Artificial cells capable of reorganizing internal chemistry, redistributing components, or sustaining metabolic‐like cycles will require deeper mechanistic control over phase behavior, membrane dynamics, and the coordination of multiple reaction layers.

Ultimately, the field is moving toward synthetic systems that integrate metabolic turnover, information processing, and adaptive mechanics within unified architectures. Progress in energy efficiency, waste regulation, hierarchical signalling, and dynamic compartmentalization will determine how closely these constructs approach the functional complexity of living matter. Meeting these challenges will not only sharpen our understanding of biological organization far from equilibrium, but also enable transformative technologies based on autonomous, stimuli‐responsive soft matter.

Conflicts of Interest

The authors declare no conflict of interest.

Biographies

Antonio Aguanell studied Chemistry at the Universidad de Alcalá and completed a Master's in Organic Chemistry at the Universidad Complutense de Madrid. He has consistently worked at the interface of chemistry and biology, gaining experience in smart materials and medicinal chemistry. In 2024, he joined Ruth Pérez's group at the Margarita Salas Biological Research Center (CIB‐CSIC), where he is pursuing his PhD on drug discovery using dynamic combinatorial chemistry.

Álvaro Sarabia‐Vallejo obtained a Degree in Pharmacy and a PhD in Medicinal Chemistry from the Faculty of Pharmacy from Complutense University of Madrid where he is now a teaching assistant. His research interests involve organic synthesis, UV‐Vis spectroscopy and fluorescence imgaing applied to medicinal chemistry. In 2025, he joined the Ruth Pérez's Biological Systems Chemistry group at Margarita Salas Biological Research Center as a postdoctoral researcher where he currently studies covalent protein modifications.

Marc Hennebelle obtained his PhD in supramolecular chemistry from Aix‐Marseille University, 2020 and conducted postdoctoral research in Lyon on dynamic combinatorial chemistry and CO₂‐responsive systems. Since 2024, he has joined Ruth Pérez's group at CSIC Madrid on an ERC project. His research interests lie at the interface of organic, supramolecular, and biological chemistry, with a particular focus on adaptive materials and dynamic covalent frameworks for enzyme regulation and RNA recognition.

Ruth Pérez‐Fernández received her Ph.D. in Chemistry from the Autonoma University of Madrid and completed postdoctoral research with Prof. J.K.M. Sanders at the University of Cambridge on dynamic combinatorial chemistry. In 2009, she joined the Spanish National Research Council (CSIC). Since 2015, she has been working at Margarita Salas Biological Research Center, where she established the Biological Systems Chemistry group. Her research focuses on the interface of Chemistry and Biology, exploring how dynamic chemical systems function in biological environments to modulate proteins and nucleic acids.

Aguanell A., Sarabia‐Vallejo Á., Hennebelle M., and Pérez‐Fernández R., “Stimuli‐Responsive Chemical Systems That Mimic Biological Dynamics.” Chemistry – A European Journal 32, no. 1 (2026): e02993. 10.1002/chem.202502993

Data Availability Statement

This review relies on existing published studies, all cited within the manuscript. The data supporting this work can be found in the referenced sources: