Enabling the carbon loop with economical C1-based medium-chain fatty acid biomanufacturing

Abstract

Medium-chain fatty acids (MCFAs) are critical industrial chemicals, yet their production predominantly relies on fossil fuels or edible feedstocks, posing a trade-off between decarbonization goals and food security. While one-carbon (C1) substrates offer a promising alternative, a comprehensive sustainability and economic assessment is lacking. Here, we develop a coupled life cycle assessment and techno-economic analysis framework that integrates bioprocess parameters, regional grids, and carbon policy constraints to evaluate C1-based MCFA biomanufacturing. The results demonstrate that CO₂-based routes achieve a 39% lower global warming potential than lignocellulosic alternatives, driven by carbon sequestration and avoidance of energy-intensive pretreatment, but subject to renewable energy integration. Economically, C1-based production becomes cost-competitive for high-value MCFAs, with carbon taxes in policy-advanced regions cutting costs by ∼20%. Fermentation yield and feedstock costs are the most critical levers for commercialization. This work establishes a transferable quantitative framework to guide carbon-neutral MCFA production and advance C1 biomanufacturing and the circular bioeconomy.

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Green foundation

1. It advances green chemistry by providing a quantitative life cycle assessment and techno-economic analysis framework to systematically evaluate and guide sustainable, carbon-neutral biomanufacturing of medium-chain fatty acids from one-carbon feedstocks like CO₂ and CH₄.

2. We demonstrate that CO₂-based production routes achieve a 39% lower global warming potential than lignocellulosic alternatives through direct carbon sequestration. Additionally, CO₂-derived medium-chain fatty acids achieve market price parity, with regional carbon taxes potentially reducing costs by ∼20%.

3. Sustainability can be enhanced by integrating production with renewable energy grids and industrial CO₂ point sources to minimize emissions. Further research should leverage metabolic engineering to maximize fermentation yields and explore direct air capture for a fully circular carbon economy.

Introduction

The chemical sector accounts for approximately 9% of global fossil fuel consumption and contributes roughly 1 Gt of annual carbon dioxide (CO₂) emissions,¹ making it a critical frontier for decarbonization efforts.² In this context, biosynthesized fatty acids with specific chain lengths emerge as promising sustainable alternatives to petrochemical-derived products.³ Among these, medium-chain fatty acids (MCFAs), which are carboxylic acids containing 6 to 12 carbon atoms, stand out due to their versatile applications and favorable physicochemical properties. With a low oxygen-to-carbon ratio and a high energy density (average: 4146 kJ mol⁻¹), MCFAs suit a wide range of industries, including chemicals, biomedicine, and food. A significant technical advantage lies in their limited solubility in aqueous fermentation broths, which greatly simplify downstream separation and purification, leading to lower energy consumption and improved process economics.⁴ Driven by these attributes, the global MCFA market, valued at $8 billion by 2023,⁵ is projected to grow at a compound annual growth rate of 7.5%.^6,7 North America currently holds the largest market share (35%), while the Asia-Pacific region, led by China and India, exhibits the highest growth rates (6.3% and 5.9%, respectively), driven by increasing health awareness and disposable income.^6,7 Nevertheless, price fluctuations of traditional feedstocks such as coconut and palm oil, alongside geopolitical supply chain risks, underscore the need for more resilient and sustainable manufacturing routes.

The pursuit of sustainable MCFA production advances through third-generation (3G) biomanufacturing, which utilizes one-carbon (C1) feedstocks such as CO₂ and methane (CH₄). Among C1 substrates, CO₂ and CH₄ are selected as representative feedstocks due to their distinct roles in the global carbon cycle and their potential as carbon-neutral feedstocks.^8,9 CO₂ is the primary driver of climate change and can be transformed via electrochemical reduction to liquid intermediates such as methanol, offering a direct route for carbon sequestration.¹⁰ In contrast, CH₄ is a greenhouse gas with a 20-year global warming potential over 80 times that of CO₂,¹¹ offering a high-energy-density alternative that avoids the intensive hydrogen requirements of CO₂ reduction.¹² Decentralized CH₄ sources, including coal mine gas, stranded shale gas, and biogas from organic waste—are widely distributed but underutilized due to low flow rates, high impurity content, and the limited feasibility of centralized pipeline transport.^13–16 For example, in China, small-scale shale gas wells often experience rapid decline in production within the first few years, while biogas from urban or livestock waste is seasonally variable and primarily used for on-site heat and power, leaving much of the CH₄ unutilized. Targeting these small-scale CH₄ streams, CH₄-to-microbial protein bioconversion provides a practical solution: methanotrophic bacteria can directly assimilate CH₄ from these decentralized sources to synthesize protein-rich microbial biomass. On-site conversion of coal mine CH₄ or biogas into microbial protein not only mitigates greenhouse gas emissions but also produces high-value feed additives, while avoiding the costs and losses associated with long-distance transport and storage.^17,18 This approach therefore addresses both the economic and environmental challenges of decentralized CH₄ utilization, providing strong support for the selection of CH₄ as a feedstock in this study. The technological maturity of C1-based bioconversion has progressed significantly, enabling the efficient synthesis of a diverse portfolio of chemicals.¹⁹ This capability is exemplified by several pioneering approaches. For example, LanzaTech has commercialized a gas fermentation process that leverages engineered microbes to convert C1 feedstocks into fatty acids, with successful pilot- and commercial-scale demonstrations offering a viable pathway for sustainable MCFA production from captured carbon emissions.²⁰ Compared to biomass-dependent routes, the C1 approach offers a more stable feedstock supply, avoids the cost challenges associated with biomass collection and pretreatment, and presents a direct pathway to negative-carbon manufacturing by transforming greenhouse gases into valuable products.

Despite these promising advances, a major barrier persists because there is no unified platform to compare the sustainability and economic viability of different C1-based greenhouse gases in MCFA production pathways quantitatively and systematically, especially when considering dynamic variables such as carbon taxes and regional energy costs. These challenges impede the transition of C1 biomanufacturing from the laboratory to scaled-up production. To address this critical gap, we present an integrated assessment model combining techno-economic analysis (TEA) and life cycle assessment (LCA), incorporating sensitivity analysis to identify viable MCFA biomanufacturing pathways under different policy scenarios. Our model integrates bottom-up technical modules, designed for feedstock processing and biological conversion, with top-down policy constraints like carbon taxes, regional photovoltaic electricity pricing, and carbon intensity targets. This work aims to pinpoint strategic pathways that align stakeholder economics with climate objectives, thereby offering a quantitative baseline to guide sustainable industrial policy and R&D investment.

Results

Process design for MCFA biomanufacturing from diverse carbon sources

We developed an integrated biomanufacturing process in Aspen Plus to simulate the production of MCFAs from various carbon sources, including methanol sourced from coal, glucose extracted from food crops, glucose produced through enzymatic hydrolysis of lignocellulosic residues, methanol synthesized from the electrochemical reduction of CO₂, and CH₄ from natural gas (Fig. 1). The overall process comprises five stages: feedstock supply, biomass production, product extraction, and waste/utilities management (detailed parameters see the Methods section and SI Table S1). In the bioconversion stage, engineered microbial strains (e.g., E. coli, P. pastoris, and M. buryatense) convert these carbon sources into MCFAs under steady-state conditions, with key performance parameters such as carbon conversion efficiency detailed in SI Table S2. Downstream product extraction process initiates with solid–liquid separation for biomass recovery, followed by cell homogenization to release intracellular MCFAs. The resulting broth undergoes liquid–liquid extraction employing recyclable organic solvents to concentrate the MCFAs. Finally, distillation separates the mixture into individual products, including caproic acid (C₆H₁₂O₂), caprylic acid (C₈H₁₆O₂), capric acid (C₁₀H₂₀O₂), lauric acid (C₁₂H₂₄O₂), and a mixed MCFA stream. The comprehensive stepwise process schematic, configurations, and relevant chemical reactions are provided in SI Fig. S1–S10 and Notes S1–S3.

Fig. 1 Integrated generation-level biomanufacturing platforms for the synthesis of MCFAs. Schematic overview of five feedstock-to-product routes for producing caproic acid (C₆H₁₂O₂), caprylic acid (C₈H₁₆O₂), capric acid (C₁₀H₂₀O₂), lauric acid (C₁₂H₂₄O₂). The system boundaries include feedstock supply, conversion, and downstream purification. “Liquid sunshine” refers to an integrated CO₂-to-methanol technology that converts atmospheric CO₂ into liquid methanol via renewable energy-driven catalytic hydrogenation.¹⁰ 1G, first-generation; 2G, second-generation; 3G, third-generation; MCFAs, medium-chain fatty acids; S/L, solid–liquid; and WWT, wastewater treatment.

Sustainability assessment of MCFA biomanufacturing pathways

We commence a cradle-to-gate LCA to evaluate the environmental performance of MCFA production across generation-level biomanufacturing technologies, with particular emphasis on C1-based pathways. The analysis was based on a functional unit (FU) of 1 kg of MCFA produced. Detailed life cycle inventories (LCIs) were compiled, encompassing material or energy inputs and emissions associated with each route (SI Tables S3–S7). Nine significant impact categories from the ReCiPe 2016 method were selected for detailed comparison (Fig. 2),²¹ with results for additional categories available in SI Tables S8–S12. Results reveal that the environmental impacts are primarily driven by the production of carbon sources, nitrogen sources, and electricity consumption. Fossil-based routes exhibit the highest burdens, primarily due to pollution-intensive methanol production processes such as the high-temperature Fischer–Tropsch synthesis, which emits significant CO₂, sulfur dioxide, and metal ions.²² Regarding the second-generation (2G) lignocellulosic pathway, a biogenic carbon neutrality assumption was applied to the corncob residues. This standard accounting convention assumes that the CO₂ absorbed by the plant via photosynthesis during growth offsets the CO₂ released during subsequent processing. Consequently, the net GWP contribution from the biogenic carbon flux of corncob residues is accounted as zero.²³ Despite this, 2G pathways also show significant impacts, largely attributable to cellulase enzyme usage. For instance, the CTec3 enzyme contributes 51–95% of emissions across various impact categories. This broad range is attributed to the varying environmental hotspots within the enzyme supply chain (SI Fig. S11). Categories like land occupation and eutrophication are dominated by the agricultural stage of the fermentation media production, whereas in climate-related categories, the enzyme's contribution is relatively diluted by nitrogen production and other core bioprocess inputs.^24,25 This finding challenges the common perception of 2G biomanufacturing as inherently clean and underscores the importance of considering upstream resource inputs in sustainability evaluations.

Fig. 2 Life cycle assessment results of different biomanufacturing technologies. (a–i) Environmental impacts calculated per 1 kg of MCFAs using the ReCiPe 2016 Midpoint method. GWP, global warming potential; FD, fossil depletion; NLT, natural land transformation; TAP, terrestrial acidification potential; FETP, freshwater ecotoxicity potential; FEP, freshwater eutrophication potential; PMFP, particulate matter formation potential; POFP, photochemical oxidant formation potential; HT, human toxicity; 1G, first-generation; 2G, second-generation; and 3G, third-generation.

In contrast, CO₂-based pathways demonstrate superior environmental performance, particularly in mitigating climate change. The global warming potential (GWP) ranges from 22.16 to 24.21 kg CO₂-eq. per FU, representing a reduction of 82% compared to fossil-based routes and 39% compared to 2G pathways. This reduction is largely due to carbon sequestration during MCFA synthesis, with each FU production incorporating 32.95–33.82 kg CO₂-eq. (Fig. 2a). However, the electricity required for the process is the dominant environmental hotspot, accounting for over 43% of the total GWP. In terms of resource depletion (Fig. 2b and c), environmental quality (Fig. 2d–h), and human toxicity (Fig. 2i), CO₂-based routes consistently show the lowest values, but electricity consumption remains a dominant contributor to impacts in certain categories. Hence, while CO₂-based pathways present the most promising direction for mitigating environmental impact, their sustainability is linked to the decarbonization of the energy system.

CH₄-based pathways offer moderate benefits, with GWP ranging from 76.11 to 89.62 kg CO₂-eq. per FU, achieving only 36% reduction compared to fossil alternatives and twice that of 2G pathway. The limited performance is due to emissions from natural gas extraction and production.²⁶ Furthermore, combustion of unconverted CH₄ for combined heat and power (CHP) generation releases CO₂, accounting for nearly 44% of the system's overall emissions. These results underscore that the decarbonization potential of CH₄-based routes remains closely tied to the carbon intensity of upstream gas supply. To enhance the sustainability of the CH₄-based pathway, circular process strategies that maximize carbon utilization should be prioritized. A key approach is the biological recycling of unconverted CH₄ by capturing CH₄ in the off-gas stream from the fermentation unit and feeding it back into the bioprocess, and methanotrophic bacteria can further convert it into MCFAs, increasing overall substrate utilization and reducing greenhouse gas emissions. Process simulations indicate that improvements in CH₄ recycling efficiency can lower unconverted CH₄ emissions by 60–95%, substantially improving the life cycle GWP profile.²⁷ In parallel, residual biomass can be anaerobically digested to produce on-site biogas and nutrient-rich fertilizer. Incorporating these circular strategies not only reduces waste treatment burdens but also generates environmental displacement credits, estimated at 6.42%–15.82% of the system's burdens via economic allocation based on product market values (SI Table S13).²³ Overall, integrating gas recycling and biomass valorization could significantly improve the life cycle carbon footprint of CH₄-based MCFA biomanufacturing.

Environmental benefits of coupling renewable energy and policies

Building on the preceding findings that CO₂-based routes present the most promising environmental profile, we further quantify the life cycle carbon footprints of C1-based biomanufacturing by integrating renewable energy, national policies, and carbon capture and utilization (CCU) techniques under top-down constraints (Fig. 3). This analysis aims to identify key levers for optimizing these pathways and assessing their potential to achieve carbon neutrality.

Fig. 3 Sensitivity analysis of global warming potential for CO₂-based biomanufacturing technologies. Impact of renewable energy, national carbon policies, and carbon capture and utilization techniques on the carbon footprint of the 3G pathway. PV, photovoltaic and 3G, third-generation.

The CO₂-to-methanol technology predominantly depends on photovoltaic energy, emitting 0.087 kg CO₂-eq. per kWh. Substituting PV with wind energy (0.01 kg CO₂-eq. per kWh) further reduces the carbon footprint, approaching carbon neutrality with GWP values between 0.04 and 2.17 kg CO₂-eq. per FU. The significance of the regional energy mix is further highlighted by a cross-country comparison. When relying on grid electricity, CO₂-based routes in nations with low-carbon intensive grids, such as Iceland (5.62 kg CO₂-eq. per FU) and France (9.46 kg CO₂-eq. per FU), exhibit lower impacts. This performance is attributable to Iceland's and France's reliance on hydropower^28,29 and nuclear power,³⁰ respectively, and the nations do not depend on lignite for electricity generation. In contrast, in countries like Kazakhstan, India, and Poland, where grid electricity is heavily dependent on fossil fuels,^31–33 the GWP of the identical CO₂-based biochemical pathway is 7.40 to 9.64 times higher than in the baseline scenario. This disparity underscores that the decarbonization potential of biomanufacturing is intrinsically tied to the greening of the regional energy infrastructure. For more detailed descriptions of the carbon footprints of different electricity sources, see SI Table S14.

Furthermore, while natural gas-derived CH₄ demonstrates inferior environmental performance (Fig. 2), CCU technology offers a transformative alternative. We assessed the GWP of CO₂-derived CH₄ as a substitute for fossil-derived counterpart. When renewable electricity powers the CCU-based route, the GWP is reduced by 45.69% with PV and 92.47% with wind energy compared to the base case (Fig. 3). This indicates that CCU-coupled CH₄ production can attain carbon neutrality, positioning it as a sustainable alternative to fossil-based CH₄ production. However, the economic challenges associated with CO₂-to-CH₄ technology, including catalyst cost and system integration, remain a crucial consideration and will be a key focus of this research later.

Techno-economic analysis and the impact of carbon tax

To balance sustainability with commercial competitiveness, we evaluate the economic performance of biomanufacturing pathways at a commercial scale of 3000 tons of MCFAs per year (SI Note S1). The assumptions are given in detail in the existing literature (SI Table S15). Capital expenses were highest for third-generation (3G) biomanufacturing, with estimated costs of approximately $36 million for the CO₂-based pathway and $37 million for the CH₄-based pathway (Fig. 4a, SI Fig. S12, S13 and Tables S16–S20). For the CO₂ route, the major cost driver is the CO₂-to-methanol conversion, accounting for 57% of the overall equipment investment (Fig. 4b). While electrolyzer prices have dropped by two-thirds recently,³⁴ regional price variations persist, introducing uncertainty into future cost projections. For example, electrolyzer systems produced in the United States and Europe are, on average, 50% more expensive than those from China.³⁴ As for the CH₄-based pathways, the primary capital cost is utilities, especially boilers for combusting unconverted CH₄ to produce power, which constitutes about 30% of equipment costs.

Fig. 4 Comparative economic feasibility of different biomanufacturing pathways. Economic metrics based on a simulated plant capacity of 3000 tons per year. (a) Capital expenses for different biomanufacturing routes. (b) Proportion of equipment and installation costs attributed to MCFA production, purification, wastewater treatment, and utilities for different biomanufacturing routes. (c) Annual operating expenses categorized by raw materials, waste disposal, labor, fertilizer, carbon tax, and others for different biomanufacturing routes. (d) Annual raw material costs for different biomanufacturing routes. (e) Breakdown of minimum selling prices and deviation from market price for caprylic acid. (f) Effect of carbon tax of various countries and regions on the economic viability of the CO₂-based caprylic acid production. 1G, first-generation; 2G, second-generation; 3G, third-generation; MCFAs, medium-chain fatty acids; and WWT, wastewater treatment.

Operating expenses are predominantly influenced by feedstock costs (Fig. 4c and SI Tables S21–S25), with fossil methanol and glucose constituting the most expensive options, comprising up to 85% of feedstock spending (Fig. 4d and SI Table S13). While the 2G routes utilize low-cost lignocellulose, they incur further expenses from enzymatic hydrolysis, with commercial enzymes like CTec3 contributing roughly 20% to the total feedstock expenditures.³⁵ Conversely, the raw material costs for CO₂ and CH₄ pathways are only about 44% and 46%, respectively, of those for the 2G-based route. Although the initial utility investment for the CH₄ pathway is higher, it entirely replaces the purchasing of grid electricity, leading to lower long-term operating expenses. The reduced material expenses associated with the 3G platform emphasize the potential of C1 feedstocks and their viability as replacements for traditional carbon sources.^36–40

Current costs for higher-priced products (caprylic acid and caproic acid) derived from 3G feedstocks are below the market price benchmark, with minimum selling prices (MSP) ranging from $5.21 kg⁻¹ to $5.26 kg⁻¹. However, using 3G feedstocks to produce lower-value, bulk chemicals remains economically unviable without further cost reductions (Fig. 4e, SI Note S4, Fig. S14 and Tables S26–S30). The net income profiles further confirm the competitive potential of high-value products like caprylic acid, guiding our subsequent focus on their scalability and profitability (SI Note S5, Fig. S15 and Tables S31–S35). Although CO₂-based pathways have already achieved a 10.83% reduction in production costs, supportive policies can further optimize their economic potential. As shown in Fig. 4f and SI Fig. S16, carbon tax policies markedly affect the MSP, decreasing it by roughly 20% in countries with strong carbon tax frameworks, such as Sweden and Switzerland, underscoring the essential role of carbon pricing in aligning economic incentives with environmental objectives (SI Table S36 and Note S6). Beyond direct carbon pricing, the commercial transition is increasingly influenced by a coordinated policy mix. For example, risk-sharing mechanisms such as the European Union Innovation Fund provide up to 60% coverage of additional CAPEX and OPEX for low-carbon projects.⁴¹ Based on these reported subsidy levels, we further modeled their effect on the MCFA production processes. Our analysis (SI Fig. S17a and b) indicate that when combined subsidies reach 40%, the MSP could decrease by more than 30% relative to prevailing market benchmark. Similarly, we quantified the impact of renewable energy quotas by integrating data from the United States Environmental Protection Agency regarding retail electricity price increases.⁴² Our modeled scenarios show that even a 20% increase in renewable energy quota increases production costs by only ∼3% (SI Fig. S17c). These results demonstrate that, in our analysis, the economic benefits from carbon sourcing subsidies substantially outweigh the cost impacts of renewable energy mandates, providing a clearer view of policy effects under different regional conditions. This analysis illustrates that supportive policies can serve as a catalyst for the widespread implementation of CO₂-based biomanufacturing.⁴³ By connecting regulatory frameworks with sustainable production objectives, nations can promote low-carbon manufacturing pathways, decrease reliance on fossil resources, and develop a competitive market for MCFAs.⁴⁴

Commercializing from bottom-up and top-down approaches

We conducted a sensitivity analysis to identify the most critical levers for optimizing the economic viability of C1-based MCFA production. From a bottom-up perspective, fermentation metrics such as yield and productivity are the primary drivers of product costs (Fig. 5a, b and SI Fig. S18). Doubling the yield of MCFAs can reduce the MSP by nearly 50%, as it directly enhances carbon conversion efficiency and reduces the required amount of the carbon source. While increased productivity can lower capital expenses by reducing reactor size, its effect exhibits diminishing returns once a certain industrial threshold (1 g (L h)⁻¹) is surpassed (SI Table S2). Therefore, the engineering focus should be on maximizing production-related metrics through metabolic engineering strategies⁴⁵ such as directed evolution,⁴⁶ CRISPR-Cas9,⁴⁷ and adaptive evolution,⁴⁸ to change central carbon metabolism and enhance flux toward target products. Moreover, process innovations like high-density fermentation and continuous culture systems can optimize cell growth and product synthesis while reducing fermentation duration and associated costs.¹⁸

Fig. 5 Commercial potential of 3G biomanufacturing pathways to produce caprylic acid. (a) Sensitivity analysis of MSP for the 3G-CO₂ pathway to variations in key process parameters. (b) Sensitivity analysis of MSP for the 3G-CH₄ pathway to variations in key process parameters. (c) Effect of industrial CO₂ prices on the economic viability of the 3G-CO₂ pathway. (d) Effect of CH₄ prices from different countries and sources on the economic viability of the 3G-CH₄ pathway. 3G, third-generation; CBM, coalbed methane; LNG, liquefied natural gas; MCFAs, medium-chain fatty acids; and MSP, minimum selling price.

However, achieving low capital costs alone does not guarantee overall economic feasibility, as the carbon source supply chain constitutes a significant portion of total expenses. From a top-down perspective, CO₂ prices from different industrial sources exhibit considerable uncertainty, ranging from $5.6 to $65.9 per ton (Fig. 5c and SI Table S37). Sourcing CO₂ from liquid/gas fuel production processes ($5.6–31.8 ton⁻¹) can reduce the MSP by 11.34% to 26.37% compared to baseline scenarios. In contrast, utilizing higher-purity CO₂ from pulp and paper mills ($48.3 ton⁻¹) brings the MSP to market parity with a variation of 1.87%. This underscores the critical importance of co-location of biomanufacturing facilities with low-cost CO₂ emission points. For CH₄-based route (Fig. 5d and SI Fig. S19), the feedstock cost is tightly linked to regional energy markets. While liquefied natural gas (LNG) prices in the United States ($2.91 MMBtu⁻¹) support an MSP close to the market price, conversely, LNG prices in the United Kingdom, China, Japan, and Europe fluctuate between $11 MMBtu⁻¹ and $12.21 MMBtu⁻¹, resulting in MSPs that can be twice the market price, rendering the CH₄-based approach commercially unviable (SI Table S38). Nonetheless, decentralized CH₄ sources, such as coalbed methane from regions like the Shanxi Province, China, emerge as economically viable alternatives, offering price comparables to those of US LNG (SI Table S39). Looking forward, securing a sustainable and cost-effective carbon supply necessitates a dual strategy. In the near term, integrating CCU from industrial emissions should be implemented.^49,50 These findings emphasize the need for collaborations focused on CO₂ capture, storage, and utilization, reducing costs and promoting a sustainable supply chain.⁴⁴ For the long term, exploring emerging technologies like direct air capture (DAC) technologies and advancing electrochemical conversion of CO₂ to CH₄ are crucial for achieving a fully circular carbon economy (Fig. 5d), though their current costs require further reduction.^9,51,52

Discussion

We present a comprehensive comparative assessment framework that integrates cradle-to-gate LCA with TEA to evaluate the environmental and economic prospects of producing MCFAs across different generational feedstocks, with a focus on CO₂- and CH₄-based pathways. Our LCA results identify CO₂-to-MCFA routes as the most environmentally promising option, primarily due to carbon sequestration, which effectively closes the carbon loop by converting GHGs into valuable products. Importantly, when compared to 2G lignocellulose-based pathways which rely heavily on enzyme-assisted pretreatment, the 3G system demonstrates a distinct advantage by entirely avoiding the carbon-intensive steps of biomass hydrolysis. Specifically, the production and application of cellulolytic enzymes such as CTec3 contribute 51–95% of emissions across multiple impact categories.

Economically, 3G pathways can achieve cost competitiveness for high-value MCFAs (e.g., caprylic acid), with MSPs ranging between $5.21 and 5.26 kg⁻¹. C1-based routes are favorably placed against existing non-grain 2G alternatives for specialty markets due to C1 feedstocks reducing the raw material pretreatment costs. Notably, capital investment for CO₂-to-methanol conversion remains the primary economic barriers, consistent with challenges reported in earlier assessments of CCU plants.⁵³ Sensitivity analysis further reveals that fermentation performance exerts the strongest influence on MSP. This underscores the importance of metabolic engineering, which is comparable to advances in yeast for fatty acid production.^3,54 Moreover, the analysis demonstrates that carbon taxes can reduce MSPs by approximately 20% in regions with robust carbon pricing (e.g., Sweden and Switzerland), reinforcing the role of policy in bridging the green premium.

While CO₂-based pathways achieve superior theoretical GWP reductions, CH₄-based biomanufacturing offers practical and economic advantages in specific industrial and regional contexts. A key operational advantage is utility self-sufficiency, which enables the CHP system to operate independently of the electricity grid. Furthermore, CH₄ is particularly suitable for decentralized biomanufacturing, sourcing localized emissions such as coalbed methane, stranded shale gas, and biogas from organic waste. Unlike transporting CH₄ as LNG or compressed natural gas—which entails compression, liquefaction, and long-distance shipping costs—on-site bioconversion enables direct synthesis of high-value products, such as microbial protein, from these small-scale streams. Our analysis indicates that decentralized production near coalbed methane (CBM) or LNG sites (e.g., Shanxi Province, China) can reduce the minimum selling price of microbial protein by 11%–26%, bypassing the green premium typically associated with renewable electricity and CO₂ capture. These operational efficiencies and the generation of high-value products reinforce the competitiveness of CH₄-based pathways in regions with decentralized CH₄ resources and provide a strong rationale for its inclusion in this study. However, practical implementation faces several non-technical hurdles. Cross-enterprise coordination demands robust supply models and long-term agreements on gas purity, pricing, and lability,⁴⁴ as bioprocesses are sensitive to trace contaminants (e.g., H₂S or heavy metals).⁵⁵ From an engineering aspect, intermittent industrial gas supply challenges continuous fermentation, requiring storage systems or flexible gas-to-bioproduct strategies that may increase initial CAPEX.⁵⁶ Successful commercialization thus relies on industrial symbiosis, where waste streams become value-added feedstocks through coordinated policy support and standardized cross-sector carbon accounting.⁵⁷ Consequently, strategic feedstock selection between CO₂ and CH₄ should consider region-specific energy infrastructure and feedstock accessibility.

From a policy perspective, our results highlight the need for interventions that address both energy and carbon sourcing. Carbon tax alone is insufficient, and complementary measures, such as renewables integration mandates for industry, R&D subsidies for electrolyzer and fermentation technologies, and standards for renewable carbon in chemicals, are essential. Such multidirectional approaches can also accelerate the deployment of other green technologies, including solar and wind power.^52,58,59 Besides, the difference in environmental performance across national electricity grids underscores that global harmonization of sustainability criteria is critical.⁶⁰ Without internationally recognized accounting rules for carbon credits and renewable electricity attribution, C1-based products risk being punished in regions with carbon-intensive grids.

The primary contribution of this work lies in the development of a quantitative decision-support framework. However, a key limitation of our analysis is the lack of large-scale commercial experience with 3G platforms, which introduces uncertainty in life cycle emissions and cost estimates.⁶¹ Additionally, this study focuses exclusively on the conversion processes, emphasizing carbon sources and the related policies and conditions across different regions. While we do not claim absolute precision in the numerical findings, the primary goal of this work is to provide a rational, qualitative framework for guiding the sustainable commercial development of biomanufacturing. Further research should expand on this framework, incorporating real-world data and broader application scenarios to improve the accuracy of these estimates.

In summary, it becomes clear that C1-based MCFA biomanufacturing, when strategically combined with renewable energy and enabled by policy, represents a viable and necessary pathway toward achieving climate goals and fostering a circular economy. By quantifying the trade-offs, this work provides a critical roadmap for guiding R&D investment, shaping industrial strategy, and designing policies that unlock the full potential of carbon-neutral chemical production.

Methods

Production scale and process design

The scalability of MCFA production was evaluated using various feedstocks (methanol, glucose, corncob residues, CO₂, and CH₄) across different biomanufacturing pathways. To ensure consistency, the CO₂ inflow rate was set at 13 000 kg h⁻¹, corresponding to an annual MCFA production of 3000 tons (SI Note S1 and Table S40). This inflow rate was used to determine the necessary flow rates for other feedstocks, ensuring a consistent mass and energy balance across pathways. Detailed mass and energy balance data are provided in SI Tables S41–S70.

Process modeling was conducted using Aspen Plus version 14, with assumptions based on reported operating conditions in the literature (Table 1). To accurately describe the phase equilibria of the multi-component system, the non-random two-liquid (NRTL) activity coefficient model was employed. The NRTL model is a widely used activity coefficient model, which is particularly suitable for describing non-ideal liquid mixtures due to its ability to accurately predict liquid-phase activity coefficients and phase equilibria.^62–64 Detailed process designs, including MCFA production, purification, wastewater treatment, and utilities, are provided in SI Notes S2, S3 and Fig. S1–S10. The simulation was scaled up to determine mass balances and evaluate energy consumption, with operating conditions specified in SI Tables S71–S77.

Table 1 Assumptions for the medium-chain fatty acid (MCFA) production from unique production pathways

Parameter	Case A	Case B	Case C	Case D	Case E
Carbon inflow, kg h^−1	8 700	4 000	5 300	13 000 (ref. 65)	6 200
Carbon-to-biomass, %	86 (ref. 66)	90 (ref. 67)	90 (ref. 67)	86 (ref. 66)	60 (ref. 68)
Titer, g L^−1	2.66 (ref. 69 and 70)	3.8 (ref. 71)	0.45 (ref. 72)	2.66 (ref. 69 and 70)	0.25
Productivity, g (L h)^−1	0.13 (ref. 69 and 70)	0.16 (ref. 71)	0.01 (ref. 72)	0.13 (ref. 69 and 70)	0.005
Estimated productivity, g (L h)^−1	1.0	1.0	1.0	1.0	1.0
MCFAs content, %	15% (ref. 69)	21.05% (ref. 73)	17.5% (ref. 74)	15% (ref. 69)	14.24% (ref. 75)
Culture bacteria	P. pastoris ^70	E. coli ^71	P. putida ^70	P. pastoris ^70	M. buryatense ^71
Culture temperature	30 °C (ref. 70)	37 °C (ref. 71)	30 °C (ref. 70)	30 °C (ref. 70)	30 °C (ref. 71)
Fermentation volume, m^3	2 588	1 808	2 173	2 525	2 666
Annual capacity, tons	3 000	3 000	3 000	3 000	3 000

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Techno-economic analysis

TEA is a comprehensive method used to assess the economic and technological feasibility of MCFA production across fossil-based, 1G, 2G, and 3G feedstock platforms. The analysis was conducted using a payback approach, integrated with mass and energy balances from the Aspen Plus model. Capital expenses, operating expenses, and MSP were calculated based on a model developed by the National Renewable Energy Laboratory (NREL).⁷⁶ The TEA employed an “n^th-plant” model, which estimates the costs required for scaling up to a pre-commercial process.⁷⁶ Key assumptions and scaling factors are outlined in SI Table S15, based on the reports and studies published by the NREL.⁷⁶ Equipment costs are influenced by the MCFA production capacity, with cost scaling following a power law relative to initial prices.⁷⁷ Raw material costs, included in operating expense estimations, are listed in SI Table S13. The MSP is determined using the discounted cash flow method, where the net present value is zero, and the internal rate of return reaches 10%.⁷⁶ All costs are adjusted to 2025 US dollars to account for inflation, using the Plant Cost Index from the Chemical Engineering magazine, the Industrial Inorganic Chemical Index from SRI Consulting, and data from the US Bureau of Labor Statistics.⁷⁸

Life cycle assessment

The environmental impacts of MCFA production through the proposed pathways were evaluated using LCA to understand their effect on the environment. Following the guidelines set by the International Organization for Standardization (ISO 14040 ⁷⁹ and 14044 ⁸⁰), this study covers the four stages of LCA: goal and scope definition, life cycle inventory (LCI), life cycle impact assessment (LCIA), and interpretation. The objective was to quantify and compare the environmental impacts of producing MCFAs from different biomanufacturing platforms, evaluating their potential as alternative production methods. The system boundary was set from “cradle to gate”, and 1 kg of MCFA was used as the FU for benchmarking against similar studies. LCI data were collected from Aspen Plus simulations (SI Tables S3–S7) and fed into a simplified LCA model developed using openLCA software. The impact categories assessed include GWP (global warming potential, kg CO₂-eq.), FD (fossil depletion, kg oil-eq.), NLT (natural land transformation, m²), TAP (terrestrial acidification potential, kg SO₂-eq.), FETP (freshwater ecotoxicity potential, kg 1,4-DB-eq.), FEP (freshwater eutrophication potential, kg P-eq.), PMFP (particulate matter formation potential, kg PM₁₀-eq.), POFP (photochemical oxidant formation potential, kg NMVOC), and HT (human toxicity, kg 1,4-DB-eq.). LCIA was conducted using the ReCiPe 2016 methodology. Additional details on the background data, including the Ecoinvent version 3.6 database and providers used for LCA, can be found in SI Table S78.

In this study, the CO₂ feedstock for MCFA production was assumed to come from DAC systems. While DAC offers the advantage of using atmospheric CO₂, it requires substantial electricity, and the associated environmental impact depends strongly on the carbon intensity of the local energy supply. For instance, if the electricity comes from fossil-heavy grids, the GWP of the captured CO₂ can be significantly higher, potentially offsetting the benefits of carbon sequestration.

Author contributions

C. Z. conducted the techno-economic analysis and life cycle assessment. Q. F. conceived and designed the study. Both authors have read, revised, and approved the final version of the manuscript.

Conflicts of interest

The authors declare no competing interests.

Abbreviations

CBM	Coalbed methane
CCU	Carbon capture and utilization
CH4	Methane
CHP	Combined heat and power
C6H12O2	Caproic acid
C8H16O2	Caprylic acid
C10H20O2	Capric acid
C12H24O2	Lauric acid
CO2	Carbon dioxide
C1	One-carbon
DAC	Direct air capture
FD	Fossil depletion
FEP	Freshwater eutrophication potential
FETP	Freshwater ecotoxicity potential
FU	Functional unit
GWP	Global warming potential
HT	Human toxicity
ISO	International Organization for Standardization
LCA	Life cycle assessment
LCIA	Life cycle impact assessment
LCIs	Life cycle inventories
LNG	Liquefied natural gas
MCFAs	Medium-chain fatty acids
MSP	Minimum selling prices
NLT	Natural land transformation
NREL	National Renewable Energy Laboratory
NRTL	Non-random two-liquid
PMFP	Particulate matter formation potential
POFP	Photochemical oxidant formation potential
S/L	Solid–liquid
TAP	Terrestrial acidification potential
TEA	Techno-economic analysis
WWT	Wastewater treatment
1G	First-generation
2G	Second-generation
3G	Third-generation

Data availability

Data supporting the findings of this work are available within the paper and its supplementary information (SI). The SI provides the quantitative foundation for this study, including detailed mass and energy balance data and reaction equations for biomanufacturing pathways. It contains comprehensive LCI tables and environmental impact results. Additionally, the SI outlines the techno-economic analysis assumptions and related calculation results. Supplementary information is available. See DOI: https://doi.org/10.1039/d6gc01362g.

Acknowledgements

This work was supported by the National Key R&D Programs of China (2023YFE0106600), and the Youth Innovation Team of Shaanxi Universities. This work was inspired by early discussions with Prof. Dr. Maximilian Lackner (CIRCE Biotechnologie GmbH) and Prof. Dr. Yongjin J. Zhou (Dalian Institute of Chemical Physics), for which we are truly thankful.

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