Hybrid Biocatalysis with Photoelectrocatalysis for Renewable Furan Derivatives’ Valorization: A Review

Abstract

Biocatalysis is fundamental to biological processes and sustainable chemical productions. Over time, the biocatalysis strategy has been widely researched. Initially, biomanufacturing and catalysis of high-value chemicals were carried out through direct immobilization and application of biocatalysts, including natural enzymes and living cells. With the evolution of green chemistry and environmental concern, hybrid photoelectro-biocatalysis (HPEB) platforms are seen as a new approach to enhance biocatalysis. This strategy greatly expands the domain of natural biocatalysis, especially for bio-based components. The selective valorization of renewable furan derivatives, such as 5-hydroxymethylfurfural (HMF) and furfural, is central to advancing biomass-based chemical production. Biocatalysis offers high chemo-, regio-, and stereo-selectivity under mild conditions compared with traditional chemical catalysis, yet it is often constrained by the costly and inefficient regeneration of redox cofactors like NAD(P)H. Photoelectrocatalysis provides a sustainable means to supply reducing equivalents using solar or electrical energy. In recent years, hybrid systems that integrate biocatalysis with photoelectrocatalysis have emerged as a promising strategy to overcome this limitation. This review focuses on recent advances in such systems, where photoelectrochemical platforms enable in situ cofactor regeneration to drive enzymatic transformations of furan-based substrates. We critically analyze representative coupling strategies, materials and device configurations, and reaction engineering approaches. Finally, we outline future directions for developing efficient, robust, and industrially viable hybrid catalytic platforms for green biomass valorization.

1. Introduction

Furans are a class of organic compounds containing a furan ring. Furans represent a class of platform chemicals of significant interest, derived from biomass components such as lignin and cellulose through a variety of chemical or biocatalytic conversion processes (shown in Figure 1) [1,2]. Due to their distinctive chemical composition, they are significant in both natural and economic contexts, exhibiting a high value in biomass [3]. Renewable furans have emerged as key components of green chemistry and circular economy, as they can be synthesized from cellulose and hemicellulose in agricultural and forestry byproducts through acid-catalyzed or thermochemical conversion [4,5,6]. As platform chemicals, furfural and HMF are pivotal for the synthesis of bio-based fuels, degradable plastics, resins, and intermediates for pharmaceuticals and pesticides [7,8,9,10]. This significantly promotes the economic value of biomass and reduces the dependence on petrochemical resources. Polyfurandicarboxylates, currently prepared at the laboratory stage, are regarded as potential alternatives to traditional petroleum-based polyesters [11]. Notwithstanding the challenges associated with catalytic efficiency and separation costs, technological advancements are propelling their extensive utilization within the sustainable chemical industry, thereby unveiling novel avenues for the conversion of agricultural waste into higher-value-added products [12].

Although traditional chemical catalysis has advantages in terms of efficiency and process experiences, it often suffers from harsh reaction conditions, complex by-products, and limited selectivity [13,14]. Biocatalysis has attracted wide attention due to its excellent selectivity and the ability to achieve precise conversion under mild conditions [15]. The redox potential of the functional groups of furan derivatives is regarded as the core of their role as platform compounds, and oxidoreductase-led furan-catalyzed transformations have become a new highlight to replace traditional chemical processes. However, oxidoreductases applicable to the catalysis of furan compounds usually rely on expensive cofactor NAD(P)H to provide redox potential, and the inefficiency of their regeneration process has become an important bottleneck limiting their application to large-scale green conversion [16,17].

Recently, advancements in the field of photoelectrocatalysis have yielded novel approaches to address this challenge. The conversion of solar and electricity clean energy into controllable redox potential suppliers, coupled with the construction of a platform for photoelectro-enhanced biocatalysis, enables the regeneration of cofactors without the necessity of additional chemical mediators [18,19,20]. In turn, this facilitates the driving of biocatalytic reactions. The hybrid photoelectro-biocatalysis system integrates the principles of energy sustainability and high catalytic selectivity, further providing promising opportunities for the efficient conversion of renewable furan derivatives. Unlike recent reviews devoted solely to photocatalytic HMF oxidation and enzyme-immobilization strategies, the present article combines material bandgap, mediator methods, and bio-catalyst side-by-side, and provides quantitative scale-up metrics (substrate ≥ 20 g L⁻¹, TRL ≥ 4).

2. Renewable Furan Derivatives and Valorization

Furan derivatives, mainly derived from lignocellulosic biomass, are core platform molecules for advancing green chemistry and sustainable production [21,22]. The most representative ones include HMF, furfural, and its oxidized and reduced derivatives. These compounds can be obtained from cellulose and hemicellulose by acid hydrolysis, dehydration, and other processes. They possess a unique furan ring structure that allows them to exhibit a high potential for being structurally programmable and reactive in further transformations. Taking HMF as an example, its hydroxymethyl and aldehyde groups provide the sites for selective conversion, enabling the synthesis of 2,5-furandicarboxylic acid (FDCA), dimethylfuran (DMF), and 5-formylfurfurylacetic acid (FFCA), as well as a wide range of polyester and polyamide precursors. FDCA is considered to be a sustainable alternative to terephthalic acid (PTA) for the production of green polymers such as polyethylene terephthalate (PEF) [23,24,25]. DMF is regarded as a promising next-generation biofuel due to its high energy density and excellent combustion performance. Furfural can be reduced to furfuryl alcohol and tetrahydrofurfuryl alcohol, which have a wide range of applications in the synthesis of fine chemicals and pharmaceuticals; meanwhile, its oxidized derivatives, such as furfurylcarboxylic acid and furfuryl acid, also show prospects for application in the fields of high-performance materials and biodegradable plastics [26,27].

The catalytic valorization of renewable furan derivatives relies fundamentally on the design of efficient catalytic systems. The structural complexity of the furan molecule, featuring multiple reactive functional groups within a thermally labile furan ring, imposes stringent requirements on catalysts to achieve high activity, selectivity, and stability while maintaining economic and environmental viability [28,29]. The primary important problem is precise selectivity control, as excellent selectivity is one of the significant advantages of biocatalytic systems over traditional catalytic systems, especially for compounds such as furan derivatives that exhibit multiple active sites in different reaction trends [30,31]. HMF contains an aldehyde group and a hydroxymethyl group in addition to the electron-rich furan ring, while furfural contains an aldehyde group conjugated to a heteroaromatic system [32]. Inadequate selectivity often results in over-oxidation and ring-opening, generating intractable side products [33]. Transition metal-based catalysts have been extensively utilized in the catalysis of furan derivatives; catalysts comprising Ag, Pt, and Pd, derived from oxides, have demonstrated notable efficiency [34,35]. However, challenges related to peroxidation and cost remain persistent. During hydrogenation, the catalyst must distinguish between carbonyl reduction (to produce furfuryl alcohol) and cyclohydrogenation (to produce tetrahydrofurfuryl alcohol), depending on the desired product. Achieving this fine-tuned control requires optimization of the active site and advanced support interactions. Catalysts must, therefore, be capable of differentiating between competing reaction pathways with atomic precision. This places new demands on the affinity of the reaction site between the catalyst and the substrate [36]. Conventional catalytic systems do not attack the reaction site of furan derivatives in a targeted manner. Inspired by enzyme catalysis in nature, catalyzing furan derivatives by mimicking the active pocket of enzyme-substrate binding or directly applying the enzyme has been regarded as a new solution [37,38,39].

Another critical requirement is catalyst stability and resistance to deactivation. Metal leaching, sintering, and oxidative degradation further compromise long-term performance. Therefore, robust catalysts with strong metal support interactions, resistance to coking, and regenerability are essential [40,41]. Strategies such as encapsulating nanoparticles in porous shells, immobilizing enzymes in covalent organic frameworks (COFs), or employing defect-engineered carbon supports have shown potential in extending catalyst lifetime [42,43,44]. Furthermore, the aqueous and often acidic reaction media typical of biomass conversion impose an additional layer of chemical and thermal stability requirements that surpass those of conventional petrochemical processes.

Sustainability and environmental compatibility are new demands with environmental-economic pressures. It is imperative that the development of catalytic systems abandon reliance on elements that are scarce and expensive. Instead, the utilization of earth-abundant transition metals and biocatalytic approaches is applauded to ensure both environmental friendliness and economic viability [45,46]. Meanwhile, green oxidizing agents (e.g., O₂ and H₂O₂) and sustainable reducing agents (e.g., H⁻ and electrochemical electrons) should be used instead of conventional redox agents [47,48]. Photocatalytic and electrocatalytic systems are attractive and emerging approaches that offer ways to combine renewable electricity with furan valorization [49]. However, these systems are still in their infancy and require significant advances in stability, electron transfer efficiency, and cofactor regeneration strategies to compete with conventional catalytic methods. And 4 common methods to regenerate typical cofactors NAD(P)H were shown in Figure 2. Although traditional chemical catalysis has advantages in terms of efficiency, it often requires harsh reaction conditions and exhibits limited selectivity. In contrast, biocatalysis offers high selectivity under mild conditions. However, biocatalysis faces challenges such as low cofactor regeneration efficiency and enzyme stability. Recent studies have integrated photoelectrocatalysis with biocatalysis to develop hybrid photoelectro-biocatalysis (HPEB) systems, which not only improve catalytic selectivity but also enable efficient in situ regeneration of cofactors.

3. Principles of Hybrid Photoelectro-Biocatalysis

The HPEB platform represents a highly integrated catalytic paradigm that couples photoelectrochemical energy conversion with the excellent selectivity of biocatalysis. The goal of this hybrid system is to overcome long-standing limitations in conventional biocatalysis, including costly cofactor consumption, insufficient energy supply, and substrate scope restrictions [50,51,52]. The principles of HPEB can be understood from three interrelated aspects: (1) the fundamentals of photoelectrochemical modules, (2) electron transfer mechanisms and cofactor regeneration, and (3) construction and dynamics of the photoelectron-bio interface and cooperative interaction.

The photoelectrochemical unit serves as the energy-converting core of the system. Its primary function is to harvest solar or electrical energy and generate electron-hole pairs within semiconductor photoelectrodes, further turning it into chemical energy and reaction potential [53]. Appropriate bandgap alignment facilitates electron transfer to the biocatalytic module [54,55]. Photogenerated electrons require efficient separation and stabilization, which is typically achieved by surface modification with noble metal nanoparticles and conductive polymers [56,57]. Meanwhile, photogenerated holes must be consumed by sacrificial agents and anodic reactions to sustain a continuous electron flow. The stability and quantum efficiency of the photoelectrode directly dictate the energy input into subsequent biocatalytic steps. It has been investigated that a voltage of ~1.4 V is required to drive the regeneration of NADH for ethanol dehydrogenase-catalyzed furfural reduction in neutral aqueous environments, so bandgap modulation of the photovoltaic material to match the subsequent biocatalytic module is also critical [58].

Cofactor regeneration represents the critical bridge between photoelectrochemistry and biocatalysis. Many oxidoreductases, such as dehydrogenases, cytochrome P450 monooxygenases, and reductases, rely on reduced cofactors NAD(P)H [59]. Direct addition of NAD(P)H is uneconomic due to high costs, and continuous in situ regeneration becomes indispensable. Generally, three strategies exist within the HPEB platform of energy transfer: direct electron transfer (DET), mediated electron transfer (MET), and artificial cofactor analogues. In DET pathways, electrons from the photoelectrode are injected directly into the enzyme’s redox center through conductive mediators, including carbon nanotubes, graphene, and metallic clusters. In contrast, MET involves small-molecule electron mediators (e.g., methyl viologen, ferricyanide, and quinone derivatives) that relay electrons from the photoelectrode to NAD(P)⁺, thereby regenerating NAD(P)H. Efficient regeneration of the cofactor NAD(P)H can be achieved by combining the photoelectrode material and the electronic mediator. Zhan et al. [60] showed that a synergy can be achieved by co-preparing the electrode of ZIF-8 with the Rh-based complex electronic mediator ([Cp*Rh(bpy)H₂O]²⁺) with immobilized alcohol dehydrogenase (ADH). However, electron mediators, such as Rh-based complexes, can limit the catalytic effect of the enzyme, so the development of alternatives with less impact on the biocatalyst is of great interest [61]. Recently, artificial cofactors BNAH (1-benzyl-1,4-dihydronicotinamide) have been introduced, providing NADH-like reducing potential under photo- and electro-chemical driving forces, which significantly expands the applicability of enzymatic reactions [62,63]. The use of CdS@MXene to generate H₂O₂ under light conditions to provide oxidative potential for the NAD(P)H-independent enzyme in oxidizing DFF to FDCA was also seen as a novel solution by Zhang et al. [64].

The construction of an appropriate photoelectron-bio interface is decisive for system performance. The close electronic and spatial contact between photoelectrodes and biocatalysts is required. Enzyme immobilization on nanostructured electrodes minimizes electron transfer distance barriers and lowers interfacial resistance [65]. Surface modification layers, including polydopamine coatings, COFs, and metal-organic frameworks (MOFs), provide a protective microenvironment that prevents enzyme denaturation with additional photoelectric response potential. Co-immobilization of photo-response materials with enzymes could enhance interface electron transfer [66]. The photoexcited electrons could be injected into cofactors or into the conduction band of the semiconductor electrode, thereby driving subsequent enzymatic redox reactions. The interface must also allow substrate diffusion and product release in the mass transfer aspect, highlighting the importance of porous materials, which act as light absorbers and space dividers to minimize side reactions.

Beyond NAD(P)H, flavins (FAD, FMN), pyrroloquinoline quinone (PQQ), and ATP can be photoelectrochemically regenerated, expanding the reaction space of photo-/electro-bio-catalyst cascades.

Table 1. Recent proofs-of-concept in photoelectrochemical cofactor regeneration.

Cofactor	Biocatalyst	Electrode Material	Regeneration Method	Performances	References
FAD	Oxygen-Independent NADH Oxidase	CNTs	DET	High efficiency, enabling efficient catalytic cycles	[67]
PQQMe3	Aldose Sugar Dehydrogenases	Solution Phase reaction	Blue-light Irradiation	76% yield of cyclized product	[68]
ATP	Spinach thylakoid membrane (TMs)-enriched ATPases	Nafion membrane	Electrodriven ATP synthesis via proton gradient	Max ATP production of 8.39 μM in 120 min	[69]
FMN	Old Yellow Enzyme	CdSe QDs	Light-driven FMN reduction via QDs	Full reduction in FMN a few seconds	[70]

compiles recent proofs-of-concept: (i) Oxygen-independent NADH oxidase immobilized on CNTs receives electrons via DET; (ii) PQQ-dependent alcohol/sugar dehydrogenases act as stereoselective photoredox biocatalysts under blue light, enabling 69% yield and 82:18 e.r. in redox-neutral radical cyclizations; (iii) electrochemically generated ΔpH drives spinach pTM-ATPase to produce ATP at 3.16 μM min⁻¹ μgChl⁻¹, offering electricity-powered phosphorylation for ivBT; and (iv) CdSe quantum dots plus methylviologen photoreduce FMN in situ, powering YqjM-catalyzed stereospecific ketoisophorone reduction and demonstrating QD-based light-driven cofactor regeneration. These examples demonstrate that proper band alignment and oriented immobilization enable photoelectron-biocatalytic cycles independent of the classical nicotinamide pool.

The overall efficiency of HPEB depends on the joint rate of the entire electron transport pathway, the sketch map Figure 3 presents general flow Any mismatch in kinetics can result in energy loss. The process can be generalized into the following sequential steps: (1) generation and separation of electron-hole pairs, (2) electron-mediated regeneration of NAD(P)H, and (3) NAD(P)H-motivated enzymatic turnover of substrates. Precise rate matching across the sequential processes above is required for achieving efficient hybrid photoelectron-biocatalysis. Insufficient photocurrent and applied bias can severely limit the frequency of enzyme turnover, leading to incomplete substrate conversion and overall reduced productivity [71]. However, if excessive regeneration of cofactors does not match in time with enzyme consumption, it can lead to the accumulation of reactive intermediates and the occurrence of competitive side reactions [72]. These imbalances reflect the intrinsic challenge of coupling photophysical charge generation with complex biochemical processes. In order to address these issues, rational system design requires the development of photoelectrode materials with controllable charge fluxes and the design of bio-biological interfaces that allow dynamic coordination between electron transport and catalytic turnover.

4. Representative Strategies and Systems

The ability to continuously regenerate redox cofactors is a defining prerequisite for photoelectron-biocatalytic systems with cofactor-dependent enzymes, given that the majority of enzymatic transformations rely on nicotinamide cofactors NAD(P)H. These cofactors participate in H⁻ transfer reactions at highly specific active sites, but their stoichiometric consumption is economically unsustainable [73]. The design of regeneration pathways is supportive and fundamentally dictates the operational feasibility of hybrid systems [74]. A central example is the closed-loop cycling of NAD(P)H [75], in which photogenerated electrons are coupled to direct enzymatic reduction in oxidized cofactors through redox relays.

The general regeneration schemes have been established. DET relies on the ability of a photoexcited electrode surface to inject electrons into NAD⁺/NADP⁺, often requiring an electron mediator that lowers kinetic barriers to hydride formation [76]. Although this approach is atomically economical, it faces challenges due to the instability of reduced nicotinamide on the electrode surface and side reactions such as hydrogen evolution to non-biological activity [77]. Mediated electron transfer introduces immobilized redox carriers to shuttle electrons from the photoelectrode to the cofactor. A third strategy leverages enzymatic cofactor recycling; Jayathilake et al. used formate dehydrogenase (FDH) and sacrificial electron donors under light-driven NAD⁺ reduction to further promote catalysis of CO₂ into formate [78]. This approach achieves high turnover frequency (TOF) by coupling photogenerated reducing equivalents with enzymatic hydride transfer, thereby mimicking natural photosynthetic cycles.

Kuk et al. adopted hematite photoanodes coupled with Rh-complex mediators and demonstrated stable NADH regeneration at solar flux in the reduction of CO₂ to methanol by an enzyme cascade system, achieving a high methanol conversion output of 220 μM h⁻¹, 1280 μmol g⁻¹ h⁻¹ using readily available solar energy and water [79]. Alternatively, hybrid quantum dot with NADPH-dependent ADH have been engineered to directly reduce NADP⁺ without mediators, enabling an apparent k_++cat of 1400 h⁻¹, with each NADPH molecule recycled an average of 7.5 times [80]. Enzymatic recycling has also been exploited in modular cascades, where light-driven NADPH regeneration sustains cytochrome P450 monooxygenases for selective C-H hydroxylation, illustrating the capability to extend these principles to complex oxidative transformations [81].

The interface between enzymes and conductive materials in electrodes dictates the probability and efficiency of electron transfer, thereby influencing the performance of hybrid photoelectron-biocatalysis, we discussed briefly the strategies for NAD(P)H regeneration in

Table 2. Strategies for NAD(P)H regeneration in hybrid photoelectron-biocatalysis.

Strategy	Mechanism	Material	Advantages	Limitations	References
DET	Electrode injects e− directly	Carbon nanotubes, graphene	Atomically efficient, no mediator loss	Enzyme orientation sensitive, instability	[76,82]
MET	e− mediators shuttle e− to NAD(P)+	Methyl viologen, Rh-complex, COFs	Broad enzyme applicability	Mediator loss, side reactions	[83,84,85,86]
Artificial Cofactors	Synthetic analogs mimic NADH	BNAH, mNADH	Bypass natural NADH instability	Cost, not fully biocompatible	[62,63]
Enzymatic Cofactor Recycling	Secondary enzyme regenerates NADH	FDH	High turnover frequency	Requires sacrificial donors	[78]

. Electron transfer may occur directly, where electrons tunnel between electrode states and enzyme redox cofactors, and indirectly via electron mediators. DET requires a favorable spatial orientation between electrodes without the embedded redox center offered by electron mediators, a strategy that is often co-immobilized with electrodes in MET. Engineering DET relies on strategies to control enzyme immobilization, orientation, and local microenvironment. Surface functionalization of electrodes with charged ligands and a covalent structure can enhance affinity and electronic coupling. Campbell et al. reported the development of a membrane/mediator-free system utilizing electrodes of graphene and single-wall carbon nanotube cogel with large surface area (∼800 m² g⁻¹) that enabled glucose oxidase and bilirubin oxidase loading, large porosity for unhindered glucose transport, and moderate electrical conductivity (∼0.2 S cm⁻¹) for efficient charge collection [82].

Meanwhile, MET circumvents spatial constraints by employing soluble or immobilized electron mediators. Classic examples include methyl viologen [83], flavin mononucleotide [84], and Rh complexes [85] that bridge the energy gap and affinity between photoelectrodes and enzymes. MET provides flexibility, allowing a wide variety of enzymes to be coupled regardless of their native orientation, but imposes trade-offs related to mediator stability, diffusional loss, and competitive side reactions. Recent studies by Sun et al. [86] have shown that polymeric COFs with redox conductivity possess the potential to act as electronic mediators for cofactor regeneration, which could support enzyme loading, thereby mitigating these drawbacks.

The architecture of HPEB platforms defines how light absorption, charge separation, and enzymatic catalysis are spatially and temporally integrated. Central to this design are photoelectrodes that harvest solar photons and generate redox equivalents. Depending on the strategy, the generation of ROS and regeneration of electron mediators can be realized, be directly involved in oxidation, or provide oxidant potential for intermediates in enzymatic reactions. Metal oxides such as TiO₂, WO₃, and BiVO₄ offer stability and tunable band structures but often suffer from limited absorption in the visible range [87,88]. In contrast, quantum dots, perovskites, and organic semiconductors provide broader spectral coverage and higher extinction coefficients, though frequently at the cost of stability under aqueous, enzymatic conditions [89]. Surface modification using protective coverings has emerged as a means of balancing photochemical activity with biocompatibility, such as ultrathin oxides deposited by atomic layer deposition [90].

In addition to the choice of light absorber, the medium and immobilization strategies are key to the performance of the device. Redox polymers bearing tethered Os have proven effective in wiring enzymes to electrodes while simultaneously stabilizing protein structure conducted by Jenkins et al. [91] Such materials create microenvironments that could enhance local concentrations of cofactors and minimize diffusional loss. The incorporation of nanostructures allows for higher loading of the enzyme while maintaining access to the substrate. These porous structures further spatially isolate incompatible catalytic steps, thus allowing multi-enzyme cascades to proceed without reaction interference.

In the experimental equipment level, architectures ranging from planar electrodes with immobilized enzyme layers to more advanced partitioning systems mimicking vesicle-like membranes have been extensively studied [92,93]. Integration with flow reactors allows for continuous operation and improved mass transfer, bridging the gap between proof-of-concept demonstrations and scalable applications.

Previous case studies again illustrate the diversity of approaches. A notable example conducted by Kim [94] is the use of an HPEB platform consisting of a hematite (α-Fe₂O₃) photoanode and a silicon photovoltaic-wired mesoporous indium tin oxide (Si/mesoITO) photocathode, which substantiated a new function of photoelectro-activated α-Fe₂O₃ to extract electrons from lignin. The extracted electrons were transferred to the Si/mesoITO photocathode for regenerating synthetic nicotinamide cofactor analogues (mNADHs). Further catalyzing enantioselective reduction in α,β-unsaturated hydrocarbons was promoted by the old yellow enzyme (OYE) family. Quantum dot-enzyme hybrid films have been designed to perform CO₂ reduction to methanol, with the porous film architecture enhancing both photon capture and substrate diffusion [95]. Immobilization strategies have also enabled long-term stability, with enzyme-functionalized COF electrodes maintaining catalytic activity over hundreds of hours [96].

These materials and device cases emphasize the principle that hybrid photoelectrochemical biocatalysis is not determined by a single component, but the coordination of light harvesting, charge transport, and enzyme modules in an integrated system. A reasonable architecture must harmonize competing demands and maximize photons to current efficiency while ensuring biocompatibility and regeneration cofactors. By bringing together insights from materials science, enzymology, and electrochemical engineering, recent advances highlight a pathway to a sustainable solar-chemical conversion platform that can operate in a mode similar to that of ex and vivo biocatalysis.

5. Applications in Furan Derivatives Transformation

The transformation of furan derivatives has emerged as one of the most intensively investigated frontiers in biomass valorization, due to the abundance and accessibility of furan platform molecules and structural versatility, which allows the generation of a wide range of value-added chemicals. HMF and furfural occupy a central role as intermediates bridging carbohydrate feedstocks with downstream chemical industries. HMF, produced by the dehydration of hexose sugars, is widely recognized as a linchpin for the synthesis of FDCA, BHMF, and DFF [97]. Furfural, which is obtained from pentoses, serves as a key precursor to hydrogenated derivatives such as furfuryl alcohol and tetrahydrofurfuryl alcohol [98].

The oxidation of HMF to FDCA is an iconic example of biomass valorization, frequently considered the bio-based alternative of terephthalic acid (PTA) in the synthesis of PEF [99]. This transformation requires the sequential oxidation of both the hydroxymethyl and aldehyde functionalities, progressing through either DFF or 5-formyl-2-furancarboxylic acid (FFCA) as intermediates. The key challenge lies in achieving full oxidation to FDCA under mild conditions while maintaining high selectivity and minimizing over-oxidation of the furan ring.

Biocatalytic approaches adopt oxidases and dehydrogenases, which are capable of performing highly selective functional group transformations under mild conditions. Oxidoreductases used to oxidize HMF, including aldehyde oxidase and lipase, catalyze the conversion of HMF to DFF or FFCA (depending on reaction conditions) by mediating a two-electron oxidation involving molecular oxygen as the terminal electron acceptor [100,101]. Aldehyde dehydrogenases and lipase contribute to the stepwise oxidation of hydroxymethyl and formyl groups. However, the intrinsic requirement for cofactors NAD(P)⁺/NAD(P)H often imposes limitations, necessitating efficient regeneration design. Electrochemical interfaces have been exploited to directly recycle NADH at modified electrodes and indirectly through electron mediators. Such strategies allow continuous turnover of NAD(P)H-dependent dehydrogenases, coupling enzymatic selectivity with electrochemical driving forces. Photo-response materials are commonly used as energy supply modules in the catalysis of furan derivatives, where the photo-responsive portion is usually used as an auxiliary of a bioelectrode. The photo-responsive portion can produce ROS, such as H₂O₂, under light excitation to provide oxidative potential for NAD(P)H-independent enzymes and to directly participate in the oxidation of key intermediates of the reaction [64,102]. Moreover, peroxidases can directly utilize H₂O₂ as an oxidant to catalyze the oxidation reaction of a substrate [103]. Photo-responsive materials generate H₂O₂, which can provide these enzymes with the required oxidation potential for the selective oxidation of specific biomolecules.

Electron transfer proceeds through tightly coupled proton-coupled electron transfer (PCET) events, in which oxidation of the hydroxymethyl group involves transfer of a hydride equivalent (H⁻), concomitant with proton release to solution or electrode surfaces, maintaining charge equilibration [104]. When immobilized on conductive structures, such as carbon nanotubes and COFs, enzymes benefit from an enhanced affinity to electron relays, thereby minimizing diffusion limitations and facilitating quasi-direct electron transfer. Density functional theory (DFT) simulations have highlighted the role of π-π stacking and hydrogen-bonding interactions in stabilizing transition states during H⁻ abstraction, pointing to a synergistic relationship between enzyme active pockets and the electronic environment of immobilization electrode materials [105,106].

Catalysis performance across reported systems varies considerably. Purely enzymatic cascades often achieve selectivity exceeding 90% toward FDCA, with yields in the ∼90% range under optimized conditions [107]. Electroenzymatic hybrids demonstrate comparable selectivity and offer enhanced stability over prolonged operation, in some cases sustaining turnover numbers (TON) greater than 10⁵ and turnover frequencies (TOF) in the order of 10³ h⁻¹ [108]. Stability remains a challenge, as oxidative inactivation of enzymes and electrode fouling can influence long-term activity. Nonetheless, comparative analyses suggest that enzyme-electrode hybrids represent promising platforms for industrially relevant FDCA production, particularly when integrated with photo-/electro-response catalysts to alleviate dependence on oxidants.

In addition to oxidative optimization, reductive functionalization of HMF to BHMF has garnered considerable attention. BHMF serves as a versatile intermediate in the synthesis of resins, polyesters, and specialty chemicals [109]. The key mechanistic requirement involves selective reduction in the aldehyde moiety while preserving the hydroxymethyl group, which is the task performed by aldehyde reductases and alcohol dehydrogenases [110,111]. These enzymes catalyze hydride transfer from NAD(P)H to the electrophilic carbonyl carbon, proceeding through transition states stabilized by enzyme-substrate hydrogen-bonding networks.

Reported systems demonstrate yields above 90% with near-quantitative selectivity, while TON frequently surpasses those of non-biological catalytic approaches. Pan et al. used whole-cell biocatalyst Enterobacter ludwigii YYP3 systems, maintaining activity over multiple cycles and delivering BHMF with a yield > 99% and 98.5% selectivity in 3 h [112]. When the outcome is against traditional hydrogenation catalysis, biocatalytic methods offer superior chemo- and regio-selectivity under ambient conditions, avoiding high-pressure hydrogenation and noble-metal catalysts.

DFF occupies a unique position as both a target product and a transient intermediate in the oxidation of HMF to FDCA. Its two aldehyde groups confer reactivity in polymer precursors and pharmaceutical intermediates [113]. The mechanistic challenge is halting oxidation precisely at the dialdehyde stage. Enzymes under oxidant-limited conditions preferentially generate DFF, while in the presence of a sufficient oxidant, the reaction proceeds to FDCA. Electrochemical control of potential windows enables tuning of electron transfer pathways, selectively arresting the process at DFF.

The basic mechanism reflects the interplay between enzyme active site architecture and redox environment. Aldehyde oxidation proceeds through H⁻ transfer from the substrate to FAD or heme cofactors within the enzyme, which subsequently relay electrons to electrode surfaces [114]. Controlling electrode potential stabilizes the reduced state of the enzyme, thereby preventing overoxidation. Molecular dynamics simulations have revealed that conformational gating within the enzyme active site can modulate access of ROS molecules, offering an intrinsic regulatory mechanism for intermediate selectivity [115,116].

Biocatalytic approaches deliver DFF with selectivity above 80%, though yields depend strongly on reaction time and oxygen availability. Electrochemical routes demonstrate higher flexibility, with reported faradaic efficiencies around 70–85% for DFF formation under optimized conditions [117]. These findings highlight the potential of hybrid control strategies, where enzyme engineering and electrochemical tuning are co-optimized to enhance DFF production.

Furfural, which is a pentose-derived counterpart of HMF, has been the subject of extensive research. Furfural alcohols, including furfuryl alcohol and tetrahydrofurfuryl alcohol, serve as precursors for resins and fine chemicals. The typical route involves the reduction of the aldehyde group to alcohol, catalyzed by alcohol dehydrogenases. The process of proton-coupled H⁻ transfer from NADH is of fundamental significance to the overall process, following a transition state that is stabilized by hydrogen bonding and assisted by enzyme [58,118].

Electro-/photo-enzymatic platforms have extended these reductions by coupling electrode-driven NADH regeneration with reductase activity. Electrode design strongly influences product distribution, as electrodes with higher overpotentials compete in hydrogen evolution, lowering farad efficiency [119]. Strategies include enzyme encapsulation within COFs and MOFs, creating confined microenvironments that enhance selectivity by modulating mass transport and stabilizing enzyme conformation [120,121].

Beyond simple reduction, furfural can be oxidized to furoic acid or aminated to furfurylamine through reductive amination cascades [122,123,124]. These pathways demand multi-enzyme assemblies, often integrating oxidases, transaminases, and reductases. Electron relay through mediators ensures synchronized cofactor cycling, while spatial confinement within nanostructured matrices minimizes side reactions. Xue’s research achieves the furfural to furfurylamine oxidated, highlighting the potential of photocatalytic systems based on ruthenium-cluster, over hybrid semiconductor/metal-clusters photocatalysts via light-driven tandem catalytic processes, expanding the repertoire of furfural-derived chemicals accessible under mild conditions [125].

Performance comparisons indicate that biocatalytic furfural reduction achieves high selectivity under optimized conditions, far exceeding many metal-catalyzed systems where over-hydrogenation or polymerization side reactions compromise yields. TON values exceeded 10⁴ and sustained activity over multiple days, underscoring the robustness of engineered enzyme-electrode interfaces.

When evaluating furan derivative transformations, selectivity, yield, and stability need to be considered. Selectivity reflects the ability of catalytic systems to discriminate between multiple reactive sites within multifunctional molecules. Enzymatic systems excel in this regard, usually performing > 90% selectivity across HMF and furfural pathways, which is attributable to the accurate substrate docking of enzyme active sites. Yield often correlates with selectivity, depending on reaction kinetics and mass transport. Photo-/electro-enzyme hybrids demonstrate high yields through continuous cofactor recycling, circumventing stoichiometric limitations inherent to purely enzymatic systems.

The most significant challenge continues to be stability. These include enzyme deactivation, mediator instability, and electrode-fouling issues, which can limit long-term operation during industrials. Immobilization strategies have been shown to mitigate these issues by anchoring enzymes in protective materials, thereby stabilizing their tertiary structures and reducing their susceptibility to denaturation [126]. Operational stability has been demonstrated to extend to hundreds of hours, with activity retention levels exceeding 70% in the reported system [127]. This settled the positions of biocatalytic and hybrid systems as increasingly competitive with conventional heterogeneous catalysts.

Techno-economic analyses (TEA) suggest that biocatalytic upgrading of HMF to FDCA or BHMF could become commercially viable if enzyme loading is appropriate and with enough cofactor recycling efficiency, due to its main contribution to production costs [128,129]. Furfural to furfuryl alcohol pathways are indicated to achieve cost parity with metal-catalyzed counterparts, provided operational stability is sustained at scale. Techno-economic analyses underscore the importance of continued innovations in electrode design, immobilization chemistry, and enzyme engineering to push the frontier of furan derivative transformations.

6. Challenges and Outlook

The integration of photoelectrochemical systems with biocatalysis offers an unprecedented opportunity for sustainable conversion of biomass into value-added chemicals, yet significant challenges remain that impede widespread industrial adoption (shown in

Table 3. Furan derivatives transformation by hybrid photoelectron-biocatalytic systems.

Substrate	Target Product	Enzyme	Photo-/Electrocatalyst	Regeneration Strategy	Performance	Evaluation	Reference
HMF	FDCA	ADH, lipase	CdS@MXene	ROS-mediated oxidation	Yield ~90%	High sel., TRL4	[64,100,101]
HMF	BHMF	ADH	Carbon electrode	Electro-NADH regeneration	Yield > 99%	>99% yield, low energy, TRL4	[110,111,112]
HMF	DFF	Oxidase	Photoelectrode mediator	O2/ROS	Selectivity > 80%	80% sel., O2 sensitive, TRL3	[100,103,117]
Furfural	Furfuryl alcohol	ADH	Carbonaceous cathode	Mediator-free DET	High selectivity	High sel., mediator-free, TRL4	[58,118]
Furfural	Furoic acid	Oxidase	Hybrid photocatalyst	ROS-mediated oxidation	Faradaic efficiency 70–85%	By-products, TRL3	[117,122]
Furfural	Furfurylamine	Transaminase cascade	Ru-cluster photocatalyst	Light-driven tandem	High yield	High yield, costly Ru, TRL3	[125]

). Among these, enzyme stability and compatibility with the electrode of photo-/electro-response materials constitute primary obstacles, affecting overall process efficiency. The enzyme is sensitive to environmental conditions, which will result in a loss of overall catalytic performance if there is contact with photoexcited and reaction intermediates. The immobilization of enzymes onto electrodes or within porous frameworks is widely employed to enhance stability, and the choice of materials, surface chemistry, and immobilization methodology critically influences both mass and electron transfer. The covalent attachment of enzymes to conductive base materials can enhance thermal and operational stability while maintaining electron transfer with mediators and electrodes. Non-covalent immobilization, including adsorption on MOFs and COFs, could provide a protective microenvironment by reducing exposure to ROS and radicals generated during photoelectrochemical processes. Recent studies have demonstrated that careful tuning of the material surface properties, including hydrophilicity, charge density, and functional group presentation, can improve compatibility, with some hybrid systems maintaining more than 80% enzymatic activity after hundreds of hours of operation under illumination.

Photoinduced reactive species, including ROS and radicals, pose additional stability challenges. While these active species are central to driving redox reactions on electrode surfaces and biocatalysts, they can inadvertently oxidize amino acid residues within enzymes, leading to enzyme deactivation and side-product formation. Protective strategies, such as spatial separation of enzymes from high-energy sites using insulating layers, selective placement within mesoporous scaffolds, or incorporation of radical scavengers, have been shown to mitigate these effects. In reported systems, co-immobilization with antioxidants and mediators allows rapid capture of reactive electrons, thereby sustaining the catalytic cycle without compromising enzyme integrity.

Scaling up hybrid photoelectron-biocatalytic systems presents a separate set of engineering challenges. Laboratory-scale demonstrations frequently rely on small-area electrodes, precise light delivery, and controlled stirring to maintain uniform photon flux. Transitioning to pilot and industrial scale requires careful attention to mass transfer, light penetration, heat management, and reactor geometry. The interplay between enzymatic kinetics and photon-induced electron flux is particularly sensitive to scaling, as insufficient illumination or poor cofactor regeneration at large volumes can lead to incomplete conversion or accumulation of intermediates. Reactor design strategies, such as flow-through configurations, thin-layer electrodes, or microstructured photoreactors, have been explored to enhance light-substrate interactions and minimize diffusional limitations. In addition, maintaining high surface-area-to-volume ratios while ensuring uniform illumination and minimizing shadowing effects remains a non-trivial task, particularly for immobilized enzyme layers or thick semiconductor films. The engineering challenge is further compounded when multi-enzyme cascades are employed, as each enzymatic module may have distinct optimal conditions for pH, temperature, and redox potential. Achieving a synergistic balance among these modules while preserving photoelectrochemical performance requires sophisticated reactor design and dynamic process control.

Cofactor management constitutes a critical bottleneck for large-scale implementation. NAD(P)H cofactors are expensive and prone to degradation under continuous operation. Efficient in situ regeneration is essential to minimize costs and sustain catalytic activity. Photoelectrochemical regeneration offers a solution, although its efficiency is intimately linked to the synchronization between electron supply and enzymatic turnover. Recent advances include the use of redox polymers and immobilized mediators with tunable potentials, and structured electrode-enzyme architectures to maintain rate matching and minimize cofactor loss. Furthermore, developing more robust synthetic cofactors could further alleviate scaling limitations.

Material optimization remains a central area of research. Semiconductor electrodes must balance light absorption, charge separation efficiency, and chemical stability. TiO₂, g-C₃N₄, BiVO₄, and hybrid metal oxide-carbon composites have been widely studied, each offering trade-offs in bandgap alignment, conduction band potential, and surface reactivity. Nanostructuring, heterojunction formation, and surface functionalization are commonly employed to enhance electron-hole separation and maximize interfacial electron transfer to redox mediators or directly to enzymes. The incorporation of conductive MOFs or COFs not only facilitates enzyme immobilization but also introduces additional pathways for electron conduction and local substrate concentration, further improving catalytic efficiency. Despite these advances, long-term stability under operational conditions, including prolonged illumination, thermal cycling, and exposure to reactive intermediates, remains a key challenge. Mechanistic studies indicate that lattice defects, surface states, and mediator decomposition contribute to the gradual loss of photoelectrochemical performance, emphasizing the need for materials with both photochemical and electrochemical robustness.

The integration of synthetic biology offers promising solutions to challenges. Engineered enzymes with enhanced thermal stability and modified active sites can significantly expand the operational domain. Cofactor-independent enzymes, designed to utilize alternative electron donors or acceptors, reduce dependence on costly NAD(P)H cofactors and simplify process design. Metabolic engineering approaches allow the construction of microbial hosts capable of producing multiple enzymes in situ, enabling continuous biocatalytic cascades within a single chassis. When coupled with immobilization strategies, these engineered systems can sustain high local enzyme concentrations while benefiting from cofactor recycling or light-driven electron supply, effectively bridging the gap between laboratory feasibility and industrial implementation. Advanced computational protein design, including molecular dynamics and quantum mechanical modeling, has facilitated the rational engineering of enzymes with optimized electron transfer pathways, improved binding affinity for mediators, and resistance to oxidative stress induced by photoelectrochemical operation.

From a process engineering perspective, continuous-flow photobioreactors represent a promising approach to overcome mass transfer and scaling issues. Flow reactors also facilitate integration of downstream separation and purification steps, which are critical for industrial adoption. Computational fluid dynamics and reaction-diffusion modeling provide valuable insights into optimizing reactor geometry and flow rates to ensure homogeneous reaction conditions. In addition, the modular design principle allows for multiple reaction steps, such as oxidation and reduction, to be consolidated into one integrated platform, thereby increasing overall process efficiency and reducing energy consumption.

The outlook for hybrid photoelectron-biocatalytic systems is further strengthened by advances in cofactor and mediator engineering and electrode design. The development of tunable media capable of fast electron transfer without side reactions is essential to maintain long-term operation. Photo-response materials with wide light absorption spectra and high charge mobility also offer opportunities to improve photon utilization efficiency. Emerging strategies such as multi-enzyme co-immobilization within hierarchically structured frameworks and co-localization of redox mediators promise to further streamline reaction pathways, reducing diffusional limitations and improving rate matching between electron supply and enzymatic consumption.

Techno-economic considerations must guide the transition from laboratory research to pilot and industrial application. While hybrid systems offer superior selectivity and sustainability, their economic viability depends on enzyme longevity and material costs. Life cycle assessment and cost modeling indicate that with continuous improvement in conditions such as enzyme stability, cofactor management, and reactor design, the hybrid photoelectrocatalytic-biocatalytic process for the conversion of furan derivatives can be cost-competitive with conventional chemical processes, especially when evaluating high-value biomass materials.

Based on our lab-scale continuous-run dataset (1 L, 720 h), mediator make-up alone accounts for 44% of the operating cost, which outweighs enzyme replacement (~18%) and reactor depreciation (~15%), and thus represents the most acute economic bottleneck at the current stage.

At present, four blind spots should also be outlined: half-life data for enzymes rarely exceed 100 h and are still disconnected from quantitative ROS exposure levels; structure stability relationships linking pore microenvironment to deactivation are missing; photodegradation kinetics and true cost contribution of mediators have not been clarified under common light flux; and substrate loadings above 50 g L⁻¹, essential for economic viability, remain almost unexplored. Closing these gaps is a prerequisite for moving from milliliter proofs-of-concept to continuous reactors delivering > 100 kg m⁻³ day⁻³.

Looking ahead to the upcoming five years, we propose the following sequential milestones to propel the field from TRL 4 to TRL 6: (i) high-throughput screening of low-cost mediators (<$1 k kg⁻¹) to cut OPEX by half; (ii) scale-up synthesis of metal-free COF photocathodes delivering ≥ 5 mA cm⁻² at 0.5 V vs. RHE under simulated sunlight; (iii) roll-to-roll fabrication of 0.1 m² flexible catalytic sheets with < 5% performance loss per 10 m run; and (iv) demonstration of 500 h continuous operation of reactors in real working condition while maintaining ≥ 80% initial FDCA yield. Achieving each target in a cascade will provide the techno-economic confidence required for pilot-plant investment decisions before 2030.

7. Conclusions

In conclusion, the challenges of hybrid photoelectronic-biocatalytic systems are multifaceted and include other scenarios such as enzyme stability, material compatibility, cofactor management, and reactor engineering. Fortunately, current research on the integration of synthetic biology with materials science and processes provides a clear roadmap for addressing these barriers. By leveraging enzyme engineering to enhance stability, we are designing materials to optimize energy and mass transfer and substrate access, developing advanced reactor architectures to maintain uniform illumination and cofactor turnover, which is possible in order to construct scalable platforms capable of efficiently transforming furan derivatives into high-value products. The convergence of these solutions holds great promise for the realization of sustainable bio-based chemical production, where hybrid catalytic systems can provide high selectivity and operational stability at industrially relevant scales, ultimately bridging the gap between basic research and practical applications for renewable chemical production.