Nature‐Inspired Electrocatalysts for CO2 Reduction to C2+ Products

The electrocatalytic reduction reaction of carbon dioxide (CO2RR) has gained significant attention as a promising approach to mitigate carbon dioxide emissions and generate valuable chemicals and fuels. However, the practical application of CO2RR has been hindered by the lack of efficient and selective electrocatalysts, particularly to produce multi‐carbon (C2+) products. Nature serves as an ideal source of inspiration for the development of CO2RR electrocatalysts, as biological organisms can efficiently catalyze the same reaction and possess robust structures that are inherently scaling. In this review, recent advances in the nature‐inspired design of electrocatalysts for CO2RR to C2+ products are summarized and categorized based on their inspiration source, including the coordination sphere of metalloenzymes and the cascade reactions within the enzyme, as well as the local environment. The importance of understanding the fundamental mechanisms and the different contexts between nature and technological application in the design process is highlighted, with the aim to improve the nature‐inspired design of electrocatalysts for CO2RR to C2+ products.


Introduction
Worldwide CO 2 emissions were less than 20 gigatonnes (Gt) in 1980, but already approached 37 Gt in 2022.If this trend continues over the next few decades, net-zero CO 2 emission will be impossible to reach by 2050. [1]The electrocatalytic reduction reaction of CO 2 (CO 2 RR) using renewable electricity is gaining popularity as a potential way to address environmental problems caused by excess CO 2 , given the increasing deployment of carbon capture and utilization technologies and the decreasing price of renewable energy. [2]Among the numerous CO 2 RR products, multi-carbon (C 2+ ) products, by definition, have a greater energy density than C 1 products, as well as a high market price.

Possible Pathways and Key Factors of C 2+ Formation
CO 2 RR is a complex process that involves multi-electron and proton transfers, producing a variety of CO 2 reduction products through distinct pathways.The formation of C 2+ products usually involves four steps (Figure 1a): adsorption of CO 2 onto the catalyst surface to create *CO 2 , reduction of *CO 2 to *CO, followed by its dimerization to form C─C bonds, and, finally, desorption of the carbon products on the catalyst surface. [3]Along this pathway, *CO is considered an important intermediate because its adsorption energy is a crucial determinant of subsequent reactions, which govern the generation and selectivity of the final products.While the C─C coupling process is necessary for C 2+ production, its kinetic barrier and the competition with H─H formation through the hydrogen evolution reaction (HER) and C─H bond formation for C 1 production restrict the selectivity for targeted C 2+ products. [4]o improve the selectivity towards C 2+ products, the design of the electrocatalysts must be improved, including transport and adsorption of several CO 2 molecules onto the catalyst surface, stepwise transformation, and precise spatial positioning. [5]A relevant factor is the concentration of CO 2 and *CO at the electrocatalyst surface (Figure 1b).Studies have shown that these concentrations can influence CO 2 reduction rates and selectivity. [6]For example, when the cathode is depleted of CO 2 , the HER outperforms the CO 2 RR.However, excessive CO 2 can reduce the formation rates of C 2+ products because *CO 2 may compete with *CO for surface binding sites.Unreasonably high *CO coverage (e.g., 0.5 monolayer), [7] on the other hand, is also undesirable, because this promotes acetate production instead of ethylene and ethanol. [8]Catalyst selectivity is optimal when CO 2 and *CO concentrations are balanced.Another critical factor for C 2+ production is the intermediate-catalyst interaction. [2]Catalysts with weak *CO binding energy desorb *CO from the catalyst surface and produce carbon monoxide (CO), while catalysts with strong *CO adsorption energy might be poisoned because their surface is covered with *CO, leading to the suppression of CO 2 RR and the HER becoming the primary process. [9,10]Only catalysts with a suitable binding strength of *CO toward a certain intermediate allow *CO to be further hydrogenated and dimerized to create C 2+ products.Therefore, a balanced concentration of CO 2 and *CO and an appropriate intermediate-catalyst interaction are crucial factors for achieving high selectivity and activity in CO 2 RR for C 2+ products.
Apart from the mass transport and CO 2 concentration at the electrocatalyst surface, local pH also greatly affects the CO 2 RR. [11,12]It is worth highlighting that the local pH at the catalyst-electrolyte interface differs from the pH of the bulk electrolyte. [13]This discrepancy arises from the accelerated generation of OH − during CO 2 RR and HER, resulting in an elevated pH in close proximity to the surface of the electrocatalyst. [14]enerally, a higher local pH inhibits the HER, thereby facilitating increased Faradaic efficiencies (FEs) in the generation of C 2+ products. [12]The experimental and theoretical investigations by Chan's group demonstrate the significant impact of electrolyte pH on the activity and selectivity towards C 2+ products. [15]A pH shift from 7 to 13 results in a more-than-three-orders-ofmagnitude enhancement in C 2+ activity, accompanied by a substantial improvement in C 2+ selectivity (1-2 orders of magnitude) in the case of copper (Cu) electrocatalysts.Notably, the groups of Sinton and Sargent have successfully achieved CO 2 RR on Cu electrocatalysts in a 7 m potassium hydroxide (KOH) electrolyte (pH ≈ 15) with an ethylene partial current density of 1.3 A cm −2 and 45% cathodic energy efficiency in a flow cell. [16]

The Need for Improved Electrocatalyst Design
So far, achieving highly selective (>90%) and efficient production of C 2+ chemicals from CO 2 is a significant challenge due to both thermodynamic and kinetic limitations. [3]Moreover, a technoeconomic analysis of CO 2 RR systems reveals that C 2+ production can become profitable only once the partial current density exceeds 300 mA cm −2 . [17]For example, ethanol and n-propanol might be promising if reasonable electrocatalytic performance requirements are met (e.g., 300 mA cm −2 and 0.5 V overpotential at 70% FE).
Significant recent advancements have been made in the development of metal-based and metal-free catalysts for the CO 2 RR to C 2+ products. [18]Table 1 lists the performance of different catalysts used for CO 2 RR.Metallic catalysts provide attractive prospects for CO 2 RR due to their high electron conductivity and inherent catalytic activity.Since 1985, when Cu was first used as a CO 2 RR electrocatalyst in an aqueous system, [19] Cu has been the most extensively studied catalyst for CO 2 RR, resulting in the formation of 16 types of carbonaceous products, 12 of which are C 2 or C 3 species. [20]However, polycrystalline Cu exhibits large overpotentials, resulting in suboptimal energy efficiency and a low selectivity to specific products. [21]Other metals, such as Ag, Cr, Mo, Mn, Fe, In, and Co, have also shown promise in facilitating the production of C 2+ products. [22]Bimetallic electrocatalysts have been extensively studied for their ability to -0.7 V 0.1 m KHCO 3 [28]   Single-atom Cu on nitrogen-doped porous carbon (Cu-SA/NPC) Acetone (≈37%) -0.36 V 0.1 m KHCO 3 [29]   Copper-nitrogen-doped carbon (Cu-N-C) Ethanol (55%) -1.2 V 0.1 m CsHCO 3 [30]   Core-shell Cu@Ag Ethylene (≈32%)  [36]   Mesoporous carbon Ethanol (78%) -0.56 V 0.1 m KHCO 3 [37]   Covalent quinazoline networks (CQNs) breaking the limits of the scaling relationship during electrochemical CO 2 conversion, which can stabilize the critical intermediate and decrease the overpotential, hence increasing the selectivity towards C 2+ from CO 2 RR.Alloying Cu with a COproducing metal is thought to have synergetic effects due to the availability of C─C coupling sites (Cu) to CO-producing atoms (e.g., Au, Ag, and Zn). [23]The introduction of defects and dopants into catalysts can influence the energy barriers for specific CO 2 RR pathways, affecting the overall catalytic performance.Additionally, the use of single-atom catalysts (SACs), like carbonsupported Cu SACs, has shown potential for improving the selectivity of C 2+ product formation. [24,25]Despite these advancements, metallic catalysts still face a significant energy barrier for CO 2 activation and C─C coupling, resulting in a higher overpotential for C 2+ products generation. [3]To address this issue, metal-free electrocatalysts, such as nitrogen-doped nanodiamond (NDD), boron and nitrogen co-doped nanodiamond (BND), and nanometer-sized N-doped graphene quantum dots (NGQDs) have been developed for selective C 2+ production. [26]While metal-free materials offer unique advantages, such as abundant resources, customizable porous structures with substantial surface areas, exceptional electron conductivity, resilience under extreme conditions, and the environmental friendliness inherent to carbon, they do exhibit limitations.The sp 2 -conjugated structure composed of neutral carbon atoms renders non-polar pristine carbon materials less amenable to chemisorption interactions with CO 2 , resulting in limited CO 2 activation capabilities. [21]onsequently, the performance of metal-free materials critically hinges on defect engineering.The introduction of heteroatoms, such as nitrogen and boron, into carbon materials can effectively change the electronic properties of the carbon matrix, and significantly improve the activity of carbon electrodes by changing the charge on the carbon atoms, the adsorption energy of the CO 2 molecule, and the subsequent reaction intermediates. [27]lthough various metal-based (Cu, Cu-Au, Ni 2 P, NiGa, etc.) and metal-free (N-doped carbon, NGQDs, etc.) catalysts have been developed for CO 2 RR to C 2+ products, [3,39,40] the lack of logical design concepts for novel electrocatalysts is a barrier to further improvements.
A step-change is needed for the rational design of suitable electrocatalysts for CO 2 reduction to C 2+ products.Realizing this transformative change can be facilitated by taking cues from nature, where a vast repertoire of enzymes can catalyze the same conversion of CO 2 to valuable products with high efficiency and selectivity.This review provides an overview of efficient nature-inspired electrocatalysts towards C 2+ products based on the structure and function of metalloenzymes as well as chemically selective environments (Figure 2).Such examples are discussed in Section 2. However, reports on nature-inspired electrocatalysts for CO 2 RR to C 2+ products are scarce and often imitate isolated features of natural systems, which could result Strategies in nature that provide opportunities to inspire the development of improved electrocatalysts for CO 2 RR to C 2+ products.In the top left image, Eq and Ax refer to the covalently bound residues in the equatorial (Eq) and axial (Ax) positions in the primary-coordination sphere of an iron active center.Coordination sphere image is reproduced with permission. [48]Copyright 2019, Wiley-VCH.Spider image is reproduced with permission. [71]Copyright 2011, The Company of Biologists.Setaria leaf image is reproduced with permission. [73]Copyright 2021, American Chemical Society.
in sub-optimal CO 2 RR processes.To overcome this, a systematic methodology is needed to improve the design of CO 2 RR electrocatalysts.[43] Briefly, NICE is a stepwise design approach that involves the observation of examples of exceptional properties in natural systems that are equally desirable for a technological application of interest.Common features across examples facilitate the search for particularly effective fundamental mechanisms, hereby helping to identify nature-inspired concepts that could be adopted in technology.NICE then embeds these concepts into natureinspired designs, often assisted by computation, and which are further evolved through prototyping and experimentation towards the realization of a nature-inspired solution. [44]Thus, the four steps in the NICE methodology, prior to application, are: nature (source of inspiration), nature-inspired concept, natureinspired design, and (prototyping and) experimental realization.Throughout Section 2, the examples from recent literature on nature-inspired electrocatalysts for CO 2 RR to C 2+ products are illustrated using diagrams following these four steps, as shown in Figures 3-5.

Inspiration from the Coordination Sphere of Metalloenzymes
Metalloenzymes found in nature provide a blueprint for effectively utilizing CO 2 as a substrate and selectively generating specific products. [45]Examples of such metalloenzymes include carbon monoxide dehydrogenase (CODH), formate dehydrogenase (FDH), and nitrogenase, which use electrons as reducing equivalents to convert CO 2 into CO, formate, or hydrocarbons. [46]These enzymes have highly selective reactant binding sites, causing reactants to adopt a high-energy conformation, and increase their reactivity. [47]

Primary and Secondary Coordination Sphere
The protein scaffold surrounding the active metal centers plays a crucial role, with a structure characterized by primary and secondary coordination spheres.The primary coordination sphere involves covalent interactions between metal ions and ligands (such as -ketoglutarate or succinate in nonheme iron enzymes).The number of ligands, their bonding atom Electrocatalysts inspired by the coordination sphere of metalloenzymes for CO 2 RR to produce C 2+ products.The inspiration comes from the structure of the coordination sphere (example 1) [54] and hydrophobic properties of the secondary coordination sphere (example 2). [57]PDB ID of Moorella thermoaceticum CODH/ACS: 1MJG.Images in columns "nature-inspired design" and "experimental realization" of example 1 are reproduced with permission. [54]Copyright 2016, American Chemical Society.Images in columns "nature-inspired design" and "experimental realization" of example 2 are reproduced with permission. [57]Copyright 2020, American Chemical Society.Metalloenzyme image of example 1 is reproduced with permission. [58]opyright 2021, American Chemical Society.Coordination sphere image of example 1 is reproduced with permission. [48]Copyright 2019, Wiley-VCH.

Figure 4.
Electrocatalysts inspired by cascade reactions in natural enzyme systems (example 3) for CO 2 RR to produce C 2+ products. [59]CODH/ACS image is reproduced with permission. [62]Copyright 2021, Elsevier.Other images are reproduced under the terms of the CC-BY-NC-ND license. [59]opyright 2022, American Chemical Society.Electrocatalysts inspired by chemically selective environment of enzyme catalysis for CO 2 RR to produce C 2+ products.Inspirations are from the structure of metalloenzyme (example 4) [63] and Setaria leaf (example 5). [73]Images in columns "nature-inspired design" and "experimental realization" of example 4 are reproduced with permission. [63]Copyright 2021, American Chemical Society.Images of example 5 are reproduced with permission. [73]opyright 2021, American Chemical Society.Images in columns "nature" and "experimental realization" of example 4 are reproduced under the terms of CC-BY license. [74]Copyright 2017, MDPI.
(nitrogen/oxygen/sulfur), the oxidation state of the metal, and the overall symmetry influence how the metal's 3d orbitals split, thus affecting the orbital occupation and the spin-state ordering. [48]While the secondary coordination sphere consists of residues that do not directly bind to the active metal center but interact with the primary ligands through long-range interactions to modulate their catalytic properties. [49,50]These longrange interactions can include charge stabilization of nearby ion binding sites, hydrogen-bonding interactions and salt bridge formation involving the substrate or ligands from the primary coordination sphere, and substrate positioning by the protein and the local environment.These interactions can alter local charge distributions and the electronic configuration of the oxidant and its molecular orbitals, thereby changing the metal's redox potential, the acidity/basicity of nearby residues, and other thermodynamic properties that affect the catalytic activity of the oxidant.Additionally, proper substrate positioning ensures that the desired reaction site is closest to the oxidant, while preventing unfavorable clashes with alternative substrate sites. [14,48]his structural arrangement prevents restructuring of the active site, stabilizes it through secondary interactions, and regulates the income and outcome of reactants and products to and from the active site. [51]Applying the structural characteristics of the primary and secondary coordination spheres to CO 2 RR catalysts can enhance their catalytic activity and selectivity.How-ever, while this approach has been successful for C 1 products, few examples exist to inform the design of electrocatalysts for C 2+ products. [48,52,53]One such example is the use of a molecular copper-porphyrin complex called copper(II)-5,10,15,20tetrakis(2,6-dihydroxyphenyl)porphyrin (PorCu), which orients functional groups toward the metal active site, resulting in excellent activity and selectivity for CO 2 RR to hydrocarbons in neutral aqueous media (Figure 3, example 1). [54]When operated at -0.976 V vs the reversible hydrogen electrode (RHE), PorCu catalyst exhibited a FE of ≈17% for ethylene production from CO 2 in a CO 2 -saturated potassium bicarbonate (KHCO 3 ) electrolyte, corresponding to a turnover frequency (TOF) of 1.8 molecules per site per second for ethylene, which is attributed to the reactivity of the Cu(I) metal center and the presence of built-in hydroxyl (OH) group in the porphyrin structure.However, the partial current density at which the catalyst was able to drive the production of ethylene was only 8.4 mA cm −2 .
Therefore, it is necessary to understand the importance of the secondary coordination sphere in the design of effective electrocatalysts for C 2+ generation with the modulation of active metal center-ligand interactions and longrange interactions involving hydrogen bonding, electrostatic interactions, or van der Waals interactions, as applied to C 1 products. [52]

Hydrophobic Properties of Secondary Coordination Sphere
The secondary coordination sphere creates a specialized microenvironment with hydrophobic protein domains, which allows for precise control of the reaction environment where reactants are concentrated and bystander molecules are excluded. [55]or instance, in the CO dehydrogenase/acetyl coenzyme A synthase (CODH/ACS) enzyme complex, secondary sphere interactions play a significant influence in controlling substrate binding in ACS.The gas channel between the CODH and ACS active sites, lined by hydrophobic residues, is believed to facilitate the capture and accumulation of CO; these residues create a secondary coordination sphere that significantly reduces the energy required to bring gas molecules into close proximity with the active site of an enzyme and effectively preconcentrates the CO substrate near the active site. [45] common method for emulating the impact of the secondary coordination sphere involves utilizing partially hydrophobic polymer overcoating, which can serve as a rudimentary model of the secondary sphere and subtly bypasses the low solubility limitations of dissolved gases in aqueous solutions. [56]Wei et al. investigated the effects of polyaniline (PANI) on the selectivity and activity of copper catalysts for CO 2 reduction in the 0.1 m KHCO 3 electrolyte. [57]The study reported that coating PANI onto a Cu foil surface can to some extent suppress HER on Cu due to enhanced surface hydrophobicity and enhance the selectivity of C 2+ hydrocarbons (ethylene, ethanol, n-propanol).The FE of C 2+ hydrocarbons significantly increased from 15% on pristine Cu to 60% when a 50 nm thick PANI film was coated onto the Cu foil surface in KHCO 3 solutions (Figure 3, example 2).When Cu nanoparticles (30-50 nm) were coated with PANI (nano-Cu-PANI) instead of Cu foil, the FE of C 2+ hydrocarbons could reach up to 80%.PANI coating did not cause any changes in the morphology or chemical state of the Cu electrocatalyst, but it enriched the surface concentration of CO 2 .Furthermore, in situ attenuated total reflectance surface-enhanced infrared absorption spectroscopy spectra (ATR-SEIRAS) revealed that the PANI coating also improved the coverage and interaction of CO intermediate, facilitating CO─CO coupling.

Inspiration from Cascade Reactions in Enzymes
Nature teaches us that complex and challenging C 2+ products generation can be achieved through highly selective and efficient cascade reactions in metalloenzymes. [45]Enzymes are capable of undertaking intricate multistep cascade reactions by linking multiple distinct catalytic sites through substrate channeling. [59]An illustrative example is, again, the CODH/ACS enzyme complex. [45]These two enzymes exist as heterotetramers with two units per enzymatic site.During acyl synthesis by the CODH/ACS enzyme complex, the carbon monoxide derived from CO 2 leaves the CODH active site and enters a hydrophobic gas channel that leads to the ACS active site, where the ACS catalyzes the formation of the C─C bond. [45]Inspired by the strategy of dual active sites of enzymes, electrocatalysts that exhibit a high selectivity for reducing CO 2 to CO (CODH, Au or Ag), have been combined with another catalyst (Cu) that possesses a higher activity for converting CO to higher-order hydro-carbons for the formation of C 2+ products.For instance, a series of porphyrin-based metal complexes were used on Cu catalysts (FeTPP[Cl]/Cu), wherein the iron porphyrin serves as a CO 2 reduction catalyst selective for CO production, generating high concentrations of CO on nearby Cu atoms. [60]Density functional theory (DFT) calculations confirmed that increasing the concentration of CO near the Cu surface not only reduces the reaction energy for the C─C coupling, but also directs the selectivity from ethylene to ethanol.CO 2 reduction on FeTPP/Cu catalyst in a neutral medium with a partial current density of 124 mA cm −2 resulted in a FE of 41% at -0.82 V vs RHE for ethanol production and a full cell energy efficiency (EE) of 13%.Recently, nanocatalysts consisting of an Ag core surrounded by a porous Cu shell (Figure 4, example 3) were prepared by a two-step seed growth synthesis procedure, providing distinct active sites in nanoconfined volumes. [59]The Ag core acts as the primary active site at the bottom of the mesoporous Cu shell, whereas the Cu shell serves as both a secondary active site and a substrate channel.CO 2 is reduced to CO on the Ag, rather than on the Cu.The produced CO is then spatially confined to the Cu channel, and a bimolecular C─C coupling reaction follows, leading to the generation of higher order organic molecules.Experimental results demonstrated that n-propanol and propionaldehyde could be formed using this catalyst at potentials as low as -0.6 V versus RHE using a CO 2 -saturated KHCO 3 solution as electrolyte. [59]Previous research showed that Ag shows high catalytic activity for the conversion of CO 2 to CO at -0.60 V versus RHE but is inactive for subsequent reactions, and the relatively weak ability of Cu to activate CO 2 and produce *CO limits the C 2+ generation to a certain extent. [4,61]Thus, the Ag-Cu core-shell nanoparticles proposed by this method are equivalent to in situ coupling two reactions (CO 2 → CO and CO → C 2+ ), which would effectively provide an ample supply of *CO for the formation of C 2+ and enhances the utilization of the CO intermediate. [4]In contrast to conventional bimetallic systems where the two active sites are exposed to the electrolyte body, this enzyme-inspired substrate channel connects two different catalytic sites in one "nanozyme" to support the cascade reaction for the CO 2 RR towards C 2+ products.

Interface Enhancement for Improved Selectivity
Drawing inspiration from the structure of the enzyme, in which its active metal center is surrounded by a chemically selective environment, a novel interface enhancement strategy was developed for Cu nanoparticles (NPs) to modulate the catalytic selectivity of CO 2 RR.This strategy involved the creation of a thin layer of nitrogen-doped carbon (N x C) on the surface of Cu NPs. [63]he introduction of N x C on the Cu/N x C interface resulted in a significant increase in the FE of CO 2 RR for C 2 products (ethylene and ethanol), reaching approximately 80% at -1.1V vs RHE (Figure 5, example 4) in a 0.1 m KHCO 3 solution.The N x C environment exhibited selective enrichment and activation of CO 2 molecules through specific N-CO 2 , while leaving the electronic properties of Cu unchanged.Moreover, the robust N x C coating effectively protected the Cu substrate from morphological changes, enhancing the catalytic stability of the system.These findings highlight the importance of the chemical environment surrounding the active center.Similarly, a polycrystalline Cu electrode with an electrodeposited film formed from N-tolylpyridinium chloride in bicarbonate aqueous solution achieved a selectivity of 78.2% for C 2+ products (ethylene, ethanol, 1-propanol) at -1.1V versus RHE, which was significantly higher than FE C2+ of 26.0% on an uncoated polycrystalline Cu electrode. [64]The product profile remained the same even when the N-tolylpyridinium chloride was removed from the solution, indicating that the film was responsible for the change in selectivity.Removing or dissolving the film and then redepositing it resulted in a selectivity similar to polycrystalline Cu, indicating that the morphology of the film and the contact between the Cu surface and the film during electrodeposition affected the production of C 2+ species. [64]Another example is through the formation of a catalyst-proximal plastron layer to enhance mass transfer and CO 2 concentration near the surface of the electrocatalyst. [65]This strategy resulted in a notable decrease in the FE for hydrogen production, from 33% to 13% on smooth Cu and from 62% to 33% on nanostructured Cu.Concurrently, there was a marked enhancement in the formation of C 2+ products, including ethylene (FE of 18% using smooth Cu at −1.1 V vs RHE), propanol, and ethanol, as well as the appearance of acetone and acetate.In another notable study, Ni x P y electrocatalysts with varying ratios of phosphorus (P) and nickel (Ni) were prepared for CO 2 RR. [66]Interestingly, the selectivity of the products showed significant improvement with increasing P content, leading to the successful production and detection of methylglyoxal (C 3 ) and 2,3-furandiol (C 4 ) products for the first time.This further emphasizes the importance of the chemical composition and environment around the active site to achieve desired catalytic performance.

Hierarchical Structure with Inherent Hydrophobicity
The development of hierarchical catalysts with inherent hydrophobicity is another crucial aspect of creating a chemically selective environment.The hierarchical structure can provide significant active surface area, facilitate rapid mass transport, and accelerate electron transfer. [67]Electrocatalysts with high hydrophobicity can repel water molecules and hydrated ions from aqueous electrolytes, while maintaining high permeability to CO 2 , which is crucial for achieving high rates of CO 2 RR. [47]Otherwise, CO 2 diffusion toward the catalyst layer is hindered and high CO 2 RR rates may not be possible due to electrolyte flooding by diminished hydrophobicity.However, metallic materials often have high surface free energy, resulting in hydrophilic surfaces. [68]akerley et al. [69] utilized a unique approach to create a superhydrophobic Cu electrode with a hierarchical structure.This approach was inspired by the air bubble collection mechanism of the exceptional air-breathing spider, Argyroneta aquatica, which resides entirely underwater.This spider obtains oxygen for respiration by collecting a thin layer of air from the water surface using hydrophobic hairs on its abdomen and releases it under a dome-shaped web, forming an air-filled diving bell.This diving bell functions as a repository and also as a physical gill by absorbing dissolved oxygen from the water, enabling Argyroneta aquatica to remain submerged for up to 24 h. [70,71]A similar multiscale hydrophobic surface was obtained by modifying the hierarchical structure of dendritic Cu with a monolayer of waxy alkanethiol, resulting in an increase in the relative CO 2 /H + ratio at the three-phase interface and a concomitant increase in the contact time of the electrically generated CO with the electrode surface. [69]Compared to the unmodified hydrophilic electrode, the hydrophobic electrode showed a significant reduction in HER with a decrease in FE from 71% to 10% in a 0.1 m cesium bicarbonate (CsHCO 3 ) electrolyte solution.It also showed an improved FE of 56% and 17% for ethylene and ethanol production at neutral pH, respectively, compared to 9% and 4% for the hydrophilic, wettable electrode.This strategy demonstrates that merely altering the environment where the reaction occurs, without changing the active site itself, can cause a dramatic shift in selectivity.However, the hydrophobic electrode has limitations in overall overpotential and can only attain current densities of <30 mA cm −2 due to reduced conductivity induced by the 1octadecanethiol modification.Furthermore, its long-term stability at current densities relevant for commercial operation is questionable.Xue et al. [72] conducted experiments to functionalize the hydrophobic 1-octadecanethiol molecules on the Cu catalyst layer of a gas diffusion electrode (GDE) in a flow electrolytic cell setup to test CO 2 reduction.The results showed that the modified Cu catalyst could withstand high current electrolysis without water flooding, achieving C 2+ FEs of over 70% in the current density range of 100 to 800 mA cm −2 (with a FE C2+ of 85.2% at 800 mA cm −2 ) using 1.0 m KOH as an electrolyte.The enhanced Cu GDE can continuously drive high current (200 mA cm −2 ) electrolysis for more than 100 h without being submerged.However, it should be noted that the cathode active area of this flow cell was limited to only 0.5 cm 2 , and the scalability of the experiment has yet to be investigated.
Chemical modifications often damage the intrinsic properties of catalysts, leading to reduced electrical conductivity.Drawing inspiration from the hydrophobic properties of Setaria leaves in nature, which allow water droplets to easily roll off after dew or rain, it can improve the hydrophobicity of catalysts without compromising their inherent properties (Figure 5, example 5).Setaria leaves have a unique micro/nanostructure with oriented needles that result in a superhydrophobic contact angle of ≈152.6°.The sharp microstructures trap air, creating an air cushion at the leaf-water interface and imparting dramatic hydrophobicity. [73]otivated by this hierarchical structure, a Cu dendritic electrode with a hierarchical structure consisting of sharp needles was designed by electrodeposition.This electrode demonstrated a high C 2+ production rate of 255 ± 5.7 mA cm −2 , a FE of 64 ± 1.4%, and operational stability of 45 h at 300 mA cm −2 . [73]his superior performance was attributed to the hierarchical Cu structure, which provided sufficient hydrophobicity and ensured a robust electrode-electrolyte interface, capable of trapping more CO 2 close to the active Cu surface and effectively resisting the electrolyte flooding even under high-speed operation.The hierarchical Cu needles maintained stable hydrophobicity for the CO 2 RR without the need for additional hydrophobic coatings.This nature-inspired catalyst creates a stable gas-liquid-solid three-phase boundary, which could enable industrial-scale electrosynthesis of multi-carbon fuels at practically relevant current density.2) is very limited and, even though initial results demonstrate their high selectivity for C 1 and C 2 products, [14,[75][76][77][78] there are still numerous challenges, such as low current density, poor selectivity to C 2+ products, mediocre stability, and low CO 2 conversion (≤ 40%), which severely restrict its applications in practice. [79]he ways in which the previous examples of nature-inspired CO 2 RR electrocatalysts were developed originally do not appear to interrelate at first sight.This is because they did not use a systematic design framework to relate the inspiration from nature to the electrocatalytic application.Instead, they focused on isolated features of biological systems with desirable properties.Whilst the results demonstrate the tremendous opportunities that inspiration from nature can provide, we feel that the potential is much larger.To tap into nature's treasure trove, we need a comprehensive understanding of how the discussed features can be integrated in the development of efficient CO 2 RR electrocatalysts.To do so, there is a need for a more systematic design framework that takes a holistic approach to nature-inspired CO 2 RR electrocatalyst development.
NICE designs (Figure 6) can achieve this by incorporating certain characteristics of natural models (by abstraction or conceptualization), which are adjusted as necessary to create natureinspired designs suitable for technical applications.These mechanisms include: 1) the use of an optimized, hierarchical network to bridge length scales, minimize transport limitations, and achieve efficient and scalable solutions; 2) careful balancing of forces at one or more scales to achieve excellent performance, such as yield and selectivity in catalysis or molecular separations; 3) the use of temporal dynamics as an organizational mechanism to produce complex functionality from simple components; and 4) the identification of universal system-wide characteristics to enhance robustness and adaptability.These ubiquitous mechanisms are summarized as four broad themes that nature frequently employs for effective, scalable solutions: (T1) hierarchical transport networks, (T2) force balancing, (T3) dynamic selforganization, and (T4) ecosystems, networks, and modularity. [44]evisiting the previous examples through a NICE lens allows to extract commonalities that should inspire new solutions by employing the systematic nature-inspired design framework.For example, the design of electrocatalysts using the coordination sphere to modulate active metal center-ligand interactions relates to theme (T2) of force balancing achieved through nano-confinement; [41] the Cu electrocatalysts inspired by the diving bell spider [69] and Setaria leaf [73] use aspect of theme (T2) to enhance catalytic activity and selectivity.Force balancing ensures that the structural stability of the catalyst is maintained during the energy-intensive CO 2 electrochemical reaction by counteracting structural degradation and loss of activity in the catalyst. [47]Hierarchical transport networks allow for efficient mass transport and electron transfer during the multi-step CO 2 RR process. [80]Therefore, nature-inspired CO 2 RR electrocatalysts that incorporate force balancing and hierarchical transport networks as nature-inspired concept can facilitate the challenging production of C 2+ products requiring the coupling of multiple carbon atoms by providing stable and efficient catalytic sites for the reaction, and reduce or avoid mass transport limitations.
The next step in the NICE approach is to incorporate natureinspired concepts into the design for the intended application.To achieve this, nature-inspired design involves computational modeling, supported by theory.While experimentation is frequently used, computationally assisted design and optimization are often neglected.Utilizing computational assistance can save time Figure 6.Example of a nature-inspired design for electrocatalysts based on the structure and function of metalloenzymes. [41]Reproduced under the terms of the CC-BY license. [41]Copyright 2020, Royal Society of Chemistry.
and achieve specific catalyst design goals more accurately.Due to the nature of NICE designs, which borrow from natural systems without directly copying any features, materials of choice and parameter values, like length and time scales, may greatly differ.For example, the lung-inspired flow field designed for polymer electrolyte membrane fuel cell (PEMFC) did not simply copy the fractal structure of mammalian lungs within an arbitrary scaling range, but it investigated a lung's unique characteristics, such as a crossover from fractal to uniform branching when the Péclet number approaches 1 in the narrowest bronchioles of the upper airway tree, resulting in the uniform distribution of oxygen, and specific scaling laws for the proportioning of diameters and lengths in successive branching generations, leading to minimization of the thermodynamic losses across its structure.Then, based on these properties of the lung, a mathematical model was developed and used to calculate the required number of fractal generations in the flow field to achieve uniform distribution of reactants across the catalyst layer, as well as optimize channel lengths and diameters. [42]Iteration on designs, supported by experimental tests and characterization should be carried out during the subsequent prototyping and experimental realization step to evaluate activity, selectivity, and stability of CO 2 RR under actual relevant conditions.

Toward Integrated, Nature-Inspired Design for CO 2 Electrocatalytic Reduction
To design electrocatalyst architectures for sequential reactions that effectively and selectively convert CO 2 into value-added C 2+ products and fuels, it is necessary to consider the catalyst environment across all length scales.While recent developments in nature-inspired electrocatalysts at nano-to microscales have been discussed, there is also significant potential in taking inspiration from nature (e.g., leaves and tissues) in the design of catalytic layers on a larger scale, relevant to devices.A good example of tak-ing inspiration from nature is a tree, which has a fractal root network that transports nutrients and a fractal, self-similar structure in its canopy (macroscale). [44]The leaves on the branches have venation structures for water and nutrient transport that transition from fractal to uniformly distributed channel architectures (mesoscale), and contain molecular complexes, e.g., chlorophyll, that catch sunlight and convert CO 2 into sugars and oxygen via photosynthesis (nanoscale).Each of these scales matters, and a holistic, multi-scale view should be incorporated in design.

Conclusions
Nature has evolved various biological systems that can efficiently convert CO 2 into useful products.Inspired by the key mechanisms of these natural processes, researchers have explored the design and synthesis of nature-inspired electrocatalysts of biological organisms involved in CO 2 RR.This review highlights recent advances in the nature-inspired design of electrocatalysts for CO 2 reduction to C 2+ products, focusing on the design principles that draw inspiration from the coordination sphere of metalloenzymes, cascade reactions in natural enzyme systems, and chemically selective environments.
Despite progress in the development of nature-inspired electrocatalysts for CO 2 RR to C 2+ products, there are still many challenges to be addressed.Firstly, the aforementioned examples imitate some isolated structures or characteristics.Next, the fundamental mechanisms underlying the activity of natural enzyme systems are not always fully understood, but progress should support their application to the design of synthetic electrocatalysts.Additionally, while many promising nature-inspired designs have been proposed, investigations to improve their scalability, stability and economic viability, especially in large-scale industrial settings, are still in their infancy.
To overcome these challenges, our knowledge of the underlying mechanisms needs to be deepened to support the development and optimization of nature-inspired electrocatalysts.Furthermore, the NICE methodology, involving an engineering design framework underpinned by fundamental mechanistic investigations to discover and apply concepts in nature provides a practical, systematic approach to facilitate innovation and design of electrocatalysts and electrochemical devices that address extant challenges.

Figure 1 .
Figure 1.a) Main pathways to produce C 2+ products and b) the key factors negatively affecting C 2+ formation during the CO 2 RR.

Figure 2 .
Figure 2.Strategies in nature that provide opportunities to inspire the development of improved electrocatalysts for CO 2 RR to C 2+ products.In the top left image, Eq and Ax refer to the covalently bound residues in the equatorial (Eq) and axial (Ax) positions in the primary-coordination sphere of an iron active center.Coordination sphere image is reproduced with permission.[48]Copyright 2019, Wiley-VCH.Spider image is reproduced with permission.[71]Copyright 2011, The Company of Biologists.Setaria leaf image is reproduced with permission.[73]Copyright 2021, American Chemical Society.

Figure 3 .
Figure 3. Electrocatalysts inspired by the coordination sphere of metalloenzymes for CO 2 RR to produce C 2+ products.The inspiration comes from the structure of the coordination sphere (example 1)[54] and hydrophobic properties of the secondary coordination sphere (example 2).[57]PDB ID of Moorella thermoaceticum CODH/ACS: 1MJG.Images in columns "nature-inspired design" and "experimental realization" of example 1 are reproduced with permission.[54]Copyright 2016, American Chemical Society.Images in columns "nature-inspired design" and "experimental realization" of example 2 are reproduced with permission.[57]Copyright 2020, American Chemical Society.Metalloenzyme image of example 1 is reproduced with permission.[58]Copyright 2021, American Chemical Society.Coordination sphere image of example 1 is reproduced with permission.[48]Copyright 2019, Wiley-VCH.

Figure 5 .
Figure5.Electrocatalysts inspired by chemically selective environment of enzyme catalysis for CO 2 RR to produce C 2+ products.Inspirations are from the structure of metalloenzyme (example 4)[63] and Setaria leaf (example 5).[73]Images in columns "nature-inspired design" and "experimental realization" of example 4 are reproduced with permission.[63]Copyright 2021, American Chemical Society.Images of example 5 are reproduced with permission.[73]Copyright 2021, American Chemical Society.Images in columns "nature" and "experimental realization" of example 4 are reproduced under the terms of CC-BY license.[74]Copyright 2017, MDPI.

Table 1 .
An overview of electrocatalysts used for CO 2 RR to C 2+ products.

Table 2 .
An overview of existing nature-inspired electrocatalysts used for CO 2 RR to C 2+ products.