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Synthetic biology drives the sustainable production of terpenoid fragrances and flavors ZHANG Mengyao, CAI Peng, ZHOU Yongjin Synthetic Biology Journal    2025, 6 (2): 334-356.   DOI: 10.12211/2096-8280.2024-057 Abstract （2977）   HTML （204）    PDF（pc） （3063KB）（2084）       Knowledge map    Save The demand for personal care products has been increasing steadily. Consumers are now seeking for products that offer enhanced functionality, natural ingredients, and superior feeling experiences. Fragrances and flavors are key components in personal care formulations. Terpenes and their derivatives dominate natural fragrances due to their diverse structures and scents, widespread availability from plants and animals, stable function, and high safety profile. The terpene fragrance market is projected to grow at an annual growth rate of 6.4%, reaching $1.01 billion by 2028, indicating a high market revenue and promising future. Currently, the acquisition of natural terpene fragrances is constrained by the long growth cycle of plants, low terpene content, and high extraction cost. Thus, there is an urgent need for developing new technology, such as synthetic biology, to achieve large-scale production of diverse fragrance compounds at an environment-friendly manner. This review explores the application and development of synthetic biology in the sustainable production of terpene fragrances, highlighting how data-driven synthetic biology and biotechnological innovations empower terpene fragrance production. It also compares classical and alternative terpenoid biosynthesis pathways, elucidating their differences and advantages, which can offer comprehensive insights for chassis design toward terpenoid efficient biosynthesis. Additionally, this review explores recent advances in terpene synthase discovery and engineering as well as cell factory construction. Furthermore, we comprehensively summarizes challenges encountered in the construction of three major types of terpene fragrance cell factories: monoterpenes, sesquiterpenes, and nor-isoprenoids, and discusses metabolic engineering strategies that can be employed to address these issues, including enzyme optimization, pathway reconstruction, and cellular detoxification. At the end, we comment the current landscape of patents and industrial competition, offering insights into future challenges and opportunities, including the hurdles of biosynthesis technology, the discovery and design of new products, as well as the market regulation and safety concerns. Table and Figures | Reference | Related Articles | Metrics

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Synthetic biology ushers cosmetic industry into the “bio-cosmetics” era ZHANG Lu’ou, XU Li, HU Xiaoxu, YANG Ying Synthetic Biology Journal    2025, 6 (2): 479-491.   DOI: 10.12211/2096-8280.2024-056 Abstract （2553）   HTML （196）    PDF（pc） （1267KB）（2530）       Knowledge map    Save The field of synthetic biology has been profoundly transformed over the past two decades due to major advances in biotechnology. Notable instances of this seismic shift can be seen in DNA sequencing, where the cost for human whole genome sequencing (WGS) has dropped by ten million-fold in the past 20 years from nearly 3 billion USD in 2003 to less than 300 USD currently. For perspective, in the field of computer technology the effects of “Moore’s Law” has drove computation cost down by a thousand-fold in the past 20 years. Significant advances in technologies underpinning synthetic biology in recent years are transforming many major industries, and one remarkable example of synthetic biology driven transformation is the cosmetics and skincare industry. Historically, changes in skincare have been driven by changes in raw materials: from ancient plant-based concoctions to industrial-era chemicals in the twentieth century, and later to the concept of “cosmeceuticals” emerged in the U.S., integrating pharmaceutical benefits into cosmetics to meet the growing demand for anti-aging skincare products. Today, there’s an increasing demand for more potent cosmetics, alongside a growing voice for environmentally sustainable production. Traditional skincare product development often involves reformulating existing ingredients, which faces limitations in efficacy. Additionally, the reliance on chemical synthesis or natural extraction methods for production poses additional environmental cost due to the use of chemical reagents and significant energy consumption. Rapid advances in biotechnology enables us to overcome such efficacy and environmental limitations through direct synthesis of biomaterials that are safer and more cost-effective than their industrial chemical counterparts. Synthetic biology tools such as AI-assisted protein design and strain engineering are enabling the production of much more potent biomaterials at industrial scales, thus providing more effective and sustainable bioactive ingredients for skincare. For example, previously expensive and hard-to-obtain compounds such as hyaluronic acid, ceramides, and collagen are now produced at a fraction of the cost compared to the previous decade. In recent years, synthesized collagen has shown that it can be designed to be humanized to minimize adverse human immune reactions, thus greatly reducing allergy and other health risks of the end product. The incorporation of biomaterials that were once exclusive to expensive therapeutics into consumer skincare product is rapidly transforming the cosmetics industry by narrowing the gap between medical-grade treatment and consumer-grade anti-aging. This trend marks a significant leap toward more effective, safer, and environmentally sustainable cosmetics products. Ultimately, the advent of synthetic biology-based cosmetics is ushering in the transitioning from traditional industrial chemical-based cosmetics to a new era of “bio-cosmetics”. Table and Figures | Reference | Related Articles | Metrics

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Advances in microbial production of liquid biofuels GUO Shuyuan, ZHANG Qiannan, Gulikezi· MAIMAITIREXIATI, YANG Yiqun, YU Tao Synthetic Biology Journal    2025, 6 (1): 18-44.   DOI: 10.12211/2096-8280.2023-040 Abstract （2034）   HTML （142）    PDF（pc） （1947KB）（1176）       Knowledge map    Save With the socioeconomic development, the dependence of human beings on fossil fuels has led to their shortage and climate change. This has created an urgent need for alternatives that are renewable and environmentally friendly, and biofuels are one of them. Nowadays, widely recognized biofuels like fuel ethanol and biodiesel face challenges in terms of their production capacity due to limitation on raw materials such as grains and edible oils and high cost as well. Hence, the integration of metabolic engineering and synthetic biology has opened avenues for utilizing diverse substrates from other renewable sources, such as solar energy, light energy, electric energy, and waste biomass. Microbial cell factories, including microalgae, bacteria, and yeast, play a crucial role in synthesizing biofuels. The review comments on the evolution of the four generations of biofuels, encompassing fuel ethanol, biodiesel, bio-gasoline, jet and aviation fuels. We also discuss how microorganisms can be explored for producing the third- and fourth-generation biofuels from a variety of unconventional substrates such as carbon dioxide, methanol, and methane, multi-energy coupling to synthesize biofuels from lignocellulose by bacterial or yeast, CO2 conversion by microalgae or electrochemical-biological systems, the conversion of methanol and methane by methyltrophic microbes, and the application of synthetic biology. Furthermore, we overview biosynthetic pathways and engineering strategies for optimizing biofuels production. These strategies can convert raw materials to various fuel products, including fatty acids and esters, advanced alcohols and esters, isoprenoids, and polyketides. Finally, we highlight some challenges in biofuels production, including raw material supply and cost issue, low production yield, and limited product variety. Meanwhile, to address these challenges, we propose corresponding solutions. For example, by optimizing carbon fixation pathways, and converting carbon dioxide into low-carbon substrates like methanol, autotrophic microorganisms, methylotrophic microorganisms, and other cell factories can utilize carbon dioxide as the major raw material to synthesize various biofuels, which can benefit the application of biofuels and further promote their industrial production. Table and Figures | Reference | Related Articles | Metrics

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Advances in biosynthesis of L-arginine using engineered microorganisms WANG Qian, GUO Shiting, XIN Bo, ZHONG Cheng, WANG Yu Synthetic Biology Journal    2025, 6 (2): 290-305.   DOI: 10.12211/2096-8280.2024-068 Abstract （1920）   HTML （117）    PDF（pc） （1555KB）（1966）       Knowledge map    Save L-arginine is an alkaline amino acid that has been used as a neutralizer, moisturizer, and antioxidant in skin care products. In addition, L-arginine is also widely used in feed, medicine, and food industries. The wide range of applications for L-arginine has garnered significant attention for its robust production. L-arginine can be produced through protein hydrolysis and microbial fermentation. However, protein hydrolysis has drawbacks, including complicated operation, high purification cost, low recovery efficiency, and environmental pollution. In contrast, the microbial fermentation can use renewable and cheap feedstock. Besides, the process is performed under mild conditions, and thus is more environmentally friendly. At present, engineered microorganisms such as Corynebacteriumglutamicum and Escherichiacoli are major producers of L-arginine, and design and construction of microbial strains is the robust production of L-arginine through microbial fermentation. Random mutagenesis and screening strategies are used to develop L-arginine producing microbial strains, which are random with uncertainties, resulting in a low-efficiency for the breeding. With the development of synthetic biotechnology, development of L-arginine producing strains is empowered by the rational design of artificial synthetic pathways and regulatory machineries, taking advantages of advanced genome editing technologies. This paper reviews the progress in the studies of the synthetic pathways and regulatory mechanisms of L-arginine production that have been discovered in different microorganisms. Synthetic biology-guided metabolic engineering strategies for improving L-arginine production in C.glutamicum and E.coli are summarized. Besides, the application of the biosensor-based high-throughput screening strategy for selecting L-arginine producing strains is introduced. Finally, potential strategies to enhancing L-arginine production and the possibility of using new carbon resources such as non-food biomass and one-carbon feedstock for L-arginine production are discussed. It is envisioned that synthetic biology-guided strain engineering will further enhance the production of L-arginine, particularly using non-food feedstock in the near future. Table and Figures | Reference | Related Articles | Metrics

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Research progress in the biosynthesis of salidroside HUANG Shuhan, MA He, LUO Yunzi Synthetic Biology Journal    2025, 6 (2): 391-407.   DOI: 10.12211/2096-8280.2024-076 Abstract （1910）   HTML （145）    PDF（pc） （1809KB）（3095）       Knowledge map    Save Salidroside, a natural product known for its anti-hypoxia, anti-oxidation, anti-inflammatory, anti-aging, and anti-tumor properties, is extensively utilized in the food, cosmetics and pharmaceutical industries. Traditionally, salidroside has been obtained through the extraction from the rhizomes and tubers of Rhodiola species, including water extraction, two-phase aqueous extraction, supercritical CO2 extraction and microwave assisted extraction. However, its low natural abundance (with the salidroside content in rhizomes and tubers of Rhodiola species ranging from 0.5% to 0.8%), coupled with escalating demand, has led to a progressive depletion of these plant resources. Given the broad application potential of salidroside, the rapid growth of market demand, and the increasing scarcity of natural resources, there is an urgent need to develop innovative synthetic approaches for this valuable compound. Chemical synthesis of salidroside is characterized by its efficiency and rapid processing time. However, the use of strong acids, bases, and catalysts with heavy metal ions in the synthesis process poses challenges for the separation of salidroside with environmental risks. In recent years, with the advancements in synthetic biology, the construction of microbial cell factories for the biosynthesis of salidroside has become a viable strategy for addressing the current supply-demand imbalance and resource scarcity associated with the natural biosynthetic pathway of salidroside. To enhance the production of salidroside biosynthesis, two major strategies can be employed. First, metabolic engineering approaches can be used to overexpress key genes in the synthesis pathways while knocking out or downregulating the expression of genes related to the bypass routes, thereby increasing precursor accumulation and enhancing the metabolic flux. Second, enzyme engineering can be applied to improve the catalytic efficiency and regioselectivity of natural glycosyltransferases, which often exhibit low activity and poor selectivity. Sequence alignment techniques can be used to identify and screen potential glycosyltransferases from various biological genomes. Additionally, protein engineering combined with computational approaches can be utilized to optimize these enzymes to meet specific requirements, ultimately improving the production of salidroside. In this comprehensive review, we systematically assess the pharmacological activities of salidroside, the plant biosynthetic pathway, the mining and screening of the enzymes, and the biosynthetic advancements in Escherichia coli and Saccharomyces cerevisiae. Additionally, we discuss the separation and purification methods of salidroside and its application potential as a synthetic intermediate in the preparation of other compounds, such as hydroxysalidroside, verbascoside and echinacoside. This review aims to enhance the understanding of the biosynthetic pathway of salidroside, thereby promoting a greener and more efficient biosynthetic approach to salidroside production. Table and Figures | Reference | Related Articles | Metrics

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Advances in small-molecule biopesticides and their biosynthesis SONG Kainan, ZHANG Liwen, WANG Chao, TIAN Pingfang, LI Guangyue, PAN Guohui, XU Yuquan Synthetic Biology Journal    2025, 6 (5): 1203-1223.   DOI: 10.12211/2096-8280.2024-078 Abstract （1834）   HTML （108）    PDF（pc） （3268KB）（1248）       Knowledge map    Save Small-molecule biopesticides, in contrast to chemically synthesized pesticides, demonstrate superior degradability in the natural environment and exert a lesser adverse impact on non-target organisms and the overall ecosystem. Consequently, the evolution of small-molecule biopesticides represents a pivotal shift for the pesticide industry towards more sustainable and environmentally benign practices, with their significance projected to escalate in the realm of agricultural production in the years ahead. Despite their potential, these pesticides are currently constrained by a limited variety and suboptimal production yields, primarily attributable to the intricate research and manufacturing processes that demand substantial time and resource investments. Moreover, the biosynthetic pathways of the majority of these small molecules remain enigmatic, posing a significant challenge to their industrial application. However, the advent of synthetic biology and metabolic engineering offers promising solutions to these impediments. This progress is not merely instrumental in deepening our understanding of the intricate synthetic mechanisms of these bioactive compounds within biological systems, but it also paves the way for augmenting their production yields. By employing microbial cell factories, these technologies enable an efficient and targeted biosynthesis of specific biopesticides, thereby overcoming the limitations associated with traditional extraction and purification methods from natural sources. Microbial cell factories not only facilitate the cost-effective and environmentally friendly large-scale production of small-molecule biopesticides but also foster the innovation of novel biopesticide varieties. This review aims to summarize the small-molecule biopesticides and some semi-synthetic pesticides derived from natural products that were registered in China from January 2000 to December 2024, including eight polyketides, twelve terpenes, four alkaloids, and five other small-molecule biopesticides. Depending on their specific uses in agricultural practices, they can be classified into insecticides, microbicide, plant growth regulators, and so on. Furthermore, this review provides a succinct overview of the representative biosynthetic pathways and the corresponding microbial cell factories that are pivotal to the production of these biopesticides. We expect that an in-depth understanding of the biosynthesis of small-molecule biopesticides will pave solid ways for further elucidation of biosynthesis pathways, yield improvement, and the discovery and application of novel biopesticides. Table and Figures | Reference | Related Articles | Metrics

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Applications of machine learning in the reconstruction and curation of genome-scale metabolic models WU Ke, LUO Jiahao, LI Feiran Synthetic Biology Journal    2025, 6 (3): 566-584.   DOI: 10.12211/2096-8280.2024-090 Abstract （1813）   HTML （169）    PDF（pc） （1727KB）（3037）       Knowledge map    Save Since the publication of the first genome-scale metabolic model (GEM) in 1999, GEMs have become an essential tool for analyzing metabolism. The models integrate genes, metabolites, and reactions for combining stoichiometric matrices with constraint-based optimization to systematically describe and simulate metabolic processes in organisms. The development of automated pipelines for reconstructing GEMs has expanded their applicability to organisms from all kingdoms of life. Additionally, GEMs can integrate kinetic parameters, thermodynamic parameters, multi-omics data and multi-cellular processes to reconstruct more accurate models, thereby improving prediction accuracy. However, the reconstruction of GEMs remains heavily dependent on pre-existing knowledge, inherently limiting their scope to currently available information. This dependency restricts our ability to fully unravel the complexity and dynamic nature of metabolism. Recent advances in machine learning have demonstrated extraordinary capabilities for biological tasks such as protein structure prediction, disease identification and GEM reconstruction with functional annotation and large-scale data integration, showcasing its power in identifying patterns and uncovering hidden relationships within biological systems. Machine learning provides a promising pathway to overcome the limitations of GEMs by expanding their applicability to areas previously constrained by data availability and complexity. This review summarizes the traditional reconstruction methods of GEMs and their applications in integrating multi-dimensional data to build multi-constraint and multi-process models. The review also focuses on key applications of machine learning in gene function annotation, pathway analysis, gap-filling prediction in the reconstruction of GEMs. Additionally, the potential of machine learning in predicting kinetic, thermodynamic, and other key biochemical parameters in the reconstruction of multi-constraint and multi-process models is discussed. By combining GEMs with machine learning innovations, researchers can improve model accuracy, enhance scalability, and gain new insights into previously elusive metabolic mechanisms, bridging gaps in metabolic knowledge, and underscoring its importance as a cornerstone for future development in systems biology and biotechnology. Table and Figures | Reference | Related Articles | Metrics

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Biosynthesis of flavonoids and their applications in cosmetics WEI Lingzhen, WANG Jia, SUN Xinxiao, YUAN Qipeng, SHEN Xiaolin Synthetic Biology Journal    2025, 6 (2): 373-390.   DOI: 10.12211/2096-8280.2024-058 Abstract （1797）   HTML （121）    PDF（pc） （1916KB）（2775）       Knowledge map    Save Flavonoids are natural ingredients commonly used in cosmetics, mainly for their antioxidant and anti-inflammatory effects, but they also present a variety of other biological activities such as antimicrobial, whitening, and anti-ultraviolet. Therefore, flavonoids have a huge application potential waiting to be explored. In this review, firstly, the numerous biological properties of flavonoids used in cosmetics, as well as examples of their applications in cosmetics are presented, with their biosynthetic pathways addressed. Then, recent advances in biosynthesis of typical flavonoids (e.g., phloretin, naringenin, apigenin, luteolin, chrysin, rutin, and anthocyanins) are reviewed and discussed, with a focus on the novel synthetic biology and metabolic engineering strategies to improve the productivity and yield of biosynthesized flavonoids, including the enhancement of precursor supply, characterization and modification of key enzymes, regulation of gene expression, and optimization of fermentation processes. With the continuous innovation of synthetic biology technology, there has been an increase in the efficiency of flavonoid biosynthesis and a significant reduction in production cost, which contributes substantially to the widespread use of flavonoids in cosmetics. However, the prevalence of poor solubility and low stability of flavonoids limits their applications in cosmetics. To address this issue, we outline the research process of two main strategies: nanocarrier technology and moiety modification. The application of these research results opens up new possibilities for the use of flavonoids in cosmetics. At the end, we discuss two major challenges in high-yield synthesis of complex flavonoids: the difficulty of key enzyme modification and the imbalance of metabolic flux. We also look forward to AI-assisted synthetic biology to address these challenges and drive the yield improvement and industrialization of flavonoid biosynthesis, providing biotechnological power for the development and innovation of the cosmetics industry. Table and Figures | Reference | Related Articles | Metrics

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Research advances in biosynthesis of hyaluronic acid with controlled molecular weights XIAO Sen, HU Litao, SHI Zhicheng, WANG Fayin, YU Siting, DU Guocheng, CHEN Jian, KANG Zhen Synthetic Biology Journal    2025, 6 (2): 445-460.   DOI: 10.12211/2096-8280.2024-062 Abstract （1727）   HTML （93）    PDF（pc） （2479KB）（950）       Knowledge map    Save Hyaluronic acid (HA), a natural linear acidic polysaccharide composed of disaccharide units of D-glucuronic acid (D-GlcA) and N-acetylglucosamine (N-GlcNAc), has been widely used in the cosmetic and medical fields. HAs with different molecular weights exhibit distinct biophysical properties. While high molecular weight HAs have stronger viscoelasticity and resistance to degradation, low molecular weight HAs demonstrate enhanced biological functions. Significant progress has been made for the industrial production of HAs, with the shift from traditional extraction from animal tissues to microbial fermentation. However, the use of the natural HA-producing species Streptococcus zooepidemicus presents challenges, such as potential pathogenicity and difficulties in molecular modifications, which limit the study on the biosynthesis of HAs with varying molecular weights. Recently, the increasing demand for specific molecular weight HAs has driven the application of metabolic engineering and synthetic biology techniques for their biosynthesis and molecular weight regulation. By identifying the key factors involved in the processes, researchers have developed various strategies to optimize the synthesis of HAs and control their molecular weights. This article first analyzes the limiting factors in the synthesis of medium and high molecular weight HAs, focusing on the genetic regulation on the synthesis pathways of HA precursors and the weakening of competitive branches. Secondly, it discusses the impact of HA synthase, precursor supply, and fermentation conditions on the synthesis of ultra-high molecular weight HAs. Finally, it summarizes the preparation strategies for low molecular weight HAs, including physical and chemical methods, enzymatic methods, and microbial direct fermentation as well. The review summarizes the latest research progress regarding challenges faced in the biosynthesis and molecular weight regulation of HAs: specifically, the insufficient molecular weight of high molecular weight HAs, the weak synthesis capability of medium molecular weight HAs, and the poor controllability of low molecular weight HAs. It provides a systematic overview on enhancing the understanding of strategies for HA biosynthesis and molecular weight regulation, aiming to facilitate the efficient biosynthesis of HAs with controlled molecular weights. Table and Figures | Reference | Related Articles | Metrics

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Applications of protein engineering in pharmaceutical industry WEN Yanhua, LIU Hedong, CAO Chunlai, WU Ruibo Synthetic Biology Journal    2025, 6 (1): 65-86.   DOI: 10.12211/2096-8280.2024-061 Abstract （1694）   HTML （125）    PDF（pc） （2141KB）（2101）       Knowledge map    Save Protein engineering performs specific designs and modifications on proteins through directed evolution, semi-rational or rational design, computer-assisted design, and so on. The engineered proteins, with improved properties, have significant applications in food, medicine, fuel, and material industries. For the chemical and pharmaceutical industry, engineered enzymes can serve as efficient biocatalysts for the synthesis of active pharmaceutical ingredients (API) and their intermediates, aligning with the concepts and principles of green chemistry and manufacturing. For the biopharmaceutical industry, the engineering of peptide or protein modifying enzymes can boost the efficiency in preparing drug candidates, while engineered diagnostic enzymes can make detection more accurate and sensitive. Moreover, protein engineering can improve the bioactivities of biological drugs such as therapeutic enzymes and antibodies, increase stability, and mitigate immunogenic response for their safety and efficacy. Here, we review the tremendous progress in protein engineering, elucidate its importance in the research and development of chemically derived drugs and biologics, and provide examples of its applications. These examples encompass the discovery of enzymes or antibodies, the process of protein engineering, and the subsequent economic advantages. We aim to showcase the practical implementation of protein engineering in the pharmaceutical industry and facilitate technology transfer, thereby fostering seamless integration between research, development, and industrial production. Furthermore, we discuss challenges such as cost-effectiveness and market changes in the synthesis of API, and multi-target optimization, long cycle and high risk in the discovery and development of biopharmaceuticals. Finally, we look forward to the prospects of protein engineering in pharmaceutical industry. In the future, automated pipelines consisting artificial intelligence and self-driving laboratories will accelerate the design-build-test-learn cycle, leading to rapid progress in molecular design and discovery. Table and Figures | Reference | Related Articles | Metrics

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Advances in the biosynthesis of monoterpenes by yeast GAO Qi, XIAO Wenhai Synthetic Biology Journal    2025, 6 (2): 357-372.   DOI: 10.12211/2096-8280.2024-049 Abstract （1679）   HTML （167）    PDF（pc） （1642KB）（1557）       Knowledge map    Save Monoterpenoids constitute a significant subclass of terpenoids, known for their volatility and strong aromatic properties. These compounds are extensively employed across multiple sectors, including pharmaceuticals, foods, flavors, cosmetics, agriculture, and energy, due to their diverse pharmacological and biological activities. Currently, monoterpenoids are primarily sourced from plant extracts or chemical synthesis. However, low yield and high cost associated with plant extracts as well as low purity and high energy consumption with chemical synthesis cannot address the growing demand. As a result, the heterologous synthesis of monoterpenoids using microorganisms presents an alternative pathway that is efficient, sustainable, and eco-friendly. Yeasts show promise as hosts for monoterpenoid biosynthesis due to their fast growth, inherent mevalonate (MVA) pathway, and robust post-translational modification systems. Currently, the industrial production of the artemisinin precursor artemisinic acid and the sesquiterpene farnesene has been achieved using Saccharomyces cerevisiae. Advances in synthetic biology have enabled the construction of microbial cell factories for monoterpenoid synthesis. However, challenges remain in scaling up production due to limited precursor availability and monoterpene cytotoxicity. This review first introduces the foundational pathways of monoterpenoid biosynthesis in yeast, followed by discussion on engineering strategies and advancements in yeast-mediated monoterpenoid synthesis, which include enhancing the supply and utilization of acetyl coenzyme A and geranyl pyrophosphate (GPP), regulating and modifying key enzymes such as GPP synthase and monoterpene synthase, optimizing subcellular organelle localization and compartmentalization of MVA pathway genes and monoterpenoid synthases, and implementing exocytosis and tolerance engineering to mitigate monoterpene cytotoxicity. Future directions and strategies to overcome bottlenecks in microbial synthesis are explored to guide research in yeast synthesis of monoterpenoids. Table and Figures | Reference | Related Articles | Metrics

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Plant synthetic biology: new opportunities for large-scale culture of plant cells YAN Zhaotao, ZHOU Pengfei, WANG Yangzhong, ZHANG Xin, XIE Wenyan, TIAN Chenfei, WANG Yong Synthetic Biology Journal    2025, 6 (5): 1107-1125.   DOI: 10.12211/2096-8280.2024-095 Abstract （1631）   HTML （85）    PDF（pc） （1622KB）（2431）       Knowledge map    Save Plant Cell Culture (PCC) has emerged as a highly promising chassis for synthetic biology, offering a range of advantages such as short growth cycles, cost-effectiveness, absence of pathogenic risks, and abundant secondary metabolites. These features make PCC an attractive alternative for applications in medicine, food, and health. However, insufficient production efficiency due to difficulties in genetic transformation, complex regulatory networks, cell aggregation, and poor genetic stability remains a major obstacle that limits the commercialization of PCC. Synthetic biology, with its bottom-up engineering design approach, provides a powerful toolkit to address these challenges. By enabling the precise design and modification of native plant cells, synthetic biology offers innovative strategies to develop efficient and economically viable plant cell factories. In this paper, we first review the current status of PCC in synthesizing high-value compounds, particularly recombinant proteins and secondary metabolites. Recent advancements have demonstrated the potential of PCC to produce therapeutic proteins, vaccines, industrial enzymes and bioactive compounds such as alkaloids, flavonoids, and terpenoids. These successes underscore the versatility of PCC as a bioproduction platform. We then explore the role of synthetic biology in advancing PCC industrialization. Key developments include the creation of high-quality plant cell lines through genome editing tools like CRISPR/Cas9, enhancing genetic stability and metabolic efficiency. Additionally, synthetic biology has improved genetic transformation systems, overcoming a critical bottleneck in PCC. Enhanced expression systems, incorporating synthetic promoters and regulatory elements, have significantly boosted target compound yields. Furthermore, synthetic biology has expanded PCC applications by enabling the biosynthesis of heterologous compounds beyond their native metabolic pathways. Finally, we discuss future prospects, emphasizing the potential of synthetic biology to overcome current technical challenges. Emerging technologies including multi-omics integration, machine learning, and synthetic organelle development are anticipated to further enhance PCC’s scalability and efficiency. By addressing these challenges, synthetic biology will pave the way for large-scale plant cell cultivation, thereby facilitating its widespread adoption in industrial bioproduction. The convergence of PCC and synthetic biology holds immense potential for the sustainable, cost-effective, and scalable production of high-value compounds. Table and Figures | Reference | Related Articles | Metrics

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Effect of terminators on the downstream transcript unit with gene expression in Escherichiacoli REN Jiawei, ZHANG Jinpeng, XU Guoqiang, ZHANG Xiaomei, XU Zhenghong, ZHANG Xiaojuan Synthetic Biology Journal    2025, 6 (1): 213-227.   DOI: 10.12211/2096-8280.2024-046 Abstract （1576）   HTML （127）    PDF（pc） （2485KB）（1834）       Knowledge map    Save During gene transcription, RNA polymerase initiates the process by recognizing the promoter sequence, and terminates it upon recognizing the terminator sequence located at the 3′-UTR, leading to dissociation of the transcription complex. Therefore, promoters and terminators within the transcription unit play the role of initiating and terminating transcription, respectively. For downstream transcription units, in addition to the direct effect of terminating transcript read-through, the dissociation of the RNA polymerase from the terminator may affect the binding of the promoter to RNA polymerase in the subsequent transcription unit, thus indirectly altering the expression of the downstream transcription unit. This interplay between terminators and promoters across transcription units remains poorly understood, therefore, elucidating the impact of terminators on the transcriptional strength of downstream transcription units is of great significance for the precise regulation of gene expression and the development of efficient terminators. In this study, a library containing 405 different combinatorial elements (terminator-spacer-promoter) was constructed by combining nine terminators, five spacer sequences, and nine promoters using one-pot assembly technology. All combinations in the library were sequenced and analyzed in terms of fluorescence intensity based on the FlowSeq technology to establish the correlations between combinatorial sequences and downstream gene expression. The results showed that combinations of weak terminators, short spacers, and strong terminators were more favorable to enhance the expression of downstream genes, while combinations of strong terminators, long spacers, and weak terminators reduced the expression of downstream genes. Quantitative analysis of transcription revealed that weak terminators not only enhanced downstream leakage transcription (21~70-fold enhancement), but also facilitated downstream promoters to re-recruit RNA polymerase for re-promoted transcription (2~3-fold enhancement). This study has elucidated the effect and mechanism of terminators on the regulation of gene expression in the downstream transcription units, providing a design framework for the construction of gene circuits using terminators. Table and Figures | Reference | Related Articles | Metrics

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Applications and advances in the research of biosynthesis of amino acid derivatives as key ingredients in cosmetics YI Jinhang, TANG Yulin, LI Chunyu, WU Heyun, MA Qian, XIE Xixian Synthetic Biology Journal    2025, 6 (2): 254-289.   DOI: 10.12211/2096-8280.2024-060 Abstract （1522）   HTML （177）    PDF（pc） （2916KB）（2397）       Knowledge map    Save The development of synthetic biology has witnessed rapid advancements, which have significantly promoted production innovations in multiple sectors. In the cosmetics industry, the production methods of amino acid derivatives, which are a kind of pivotal raw materials in cosmetics, are experiencing groundbreaking innovations. The traditional methods for the production of amino acid derivatives have the problem of high cost, and usually generate environmental risk. Besides, the production stabilities of the target products are often unsatisfactory. The application of synthetic biology technology in the design and engineering of microbial cell factories for the bioproduction of amino acid derivatives, can greatly enhance the production efficiency and reduce the production costs of the target products. This innovative approach not only enhances the development of green biomanufacturing, but also benefits the demand of market for natural, safe, and functional cosmetic ingredients. In this review, an overall introduction to the utilization of amino acid derivatives in cosmetics industry is first provided. Subsequently, the strategies for the construction of high-producing strains for the production of amino acid derivatives are comprehensively summarized, which are basically categorized into two groups: enzyme conversion and microbial fermentation. The application of enzyme engineering, rational metabolic engineering, and random screening in the construction of microbial cell factories for the production of amino acid derivatives are systematically introduced. Moreover, the current research advancements and trends in the biosynthesis of amino acid derivatives as cosmetic raw materials are outlined. With the support of the cutting-edge technologies such as artificial intelligence, synthetic biology will further promote the production innovation process, enabling efficient and eco-friendly biomanufacturing of a wider array of cosmetic raw materials. This ongoing evolution holds immense promise for the cosmetics industry, promising a future with sustainable and innovative products. Table and Figures | Reference | Related Articles | Metrics

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Plant synthetic biology and bioproduction of human milk oligosaccharides YU Wenwen, LV Xueqin, LI Zhaofeng, LIU Long Synthetic Biology Journal    2025, 6 (5): 992-997.   DOI: 10.12211/2096-8280.2024-089 Abstract （1430）   HTML （81）    PDF（pc） （1105KB）（820）       Knowledge map    Save Human milk oligosaccharides (HMOs) are the third largest solid component in breast milk. They have a wide range of applications due to their beneficial physiological functions such as regulating the immune system, maintaining digestive health, and promoting brain development. There is a growing interest in the development of green and efficient bioproduction of HMOs via synthetic biology technologies. Recently, Patrick M. Shih’s team from the University of California, Berkeley, has engineered the model plant Nicotiana benthamiana as a photosynthetic platform for HMOs production. Specifically, the enzymes involved in HMOs biosynthesis were heterologously expressed in the cytosol to reconstruct the metabolic pathways required for HMOs bioproduction. Furthermore, they optimized the productions of HMOs by enhancing the supply of key precursors. Finally, several HMOs were successfully produced from the cost-effective raw materials CO2. The reported study provides deeper insights into the green bioproduction of HMOs, and expands the potential applications of plant synthetic biology technologies in the green and sustainable bioproduction of other dairy-based functional nutraceuticals. From the perspective of regulatory approval and industrial application, the aforementioned technology remains at the proof-of-concept stage. In contrast, an integrated approach combining CO2 capture and conversion with microbial fermentation shows greater potential for demonstrating scalable green biomanufacturing of HMOs in the near term. Table and Figures | Reference | Related Articles | Metrics

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Biosynthesis and manufacture of microbial oils and vegetable oils SU Juanjuan, ZHENG Jiawen, MIAO Runze, HAN Peng, WANG Shi’an, LI Fuli Synthetic Biology Journal    2025, 6 (5): 1167-1183.   DOI: 10.12211/2096-8280.2024-093 Abstract （1375）   HTML （58）    PDF（pc） （1718KB）（528）       Knowledge map    Save Oils and fatty acid derivatives are essential raw materials across various industries, including food, bioenergy, functional materials, and pharmaceutical chemicals, with significant global demand. Currently, China heavily relies on imported oilseed crops, and the cultivation of oil crops is constrained by limited arable land, making it difficult to meet the growing demand for oils. The development of synthetic biology offers a promising solution, particularly through the microbial oil synthesis technology, which utilizes renewable resources to produce oils, presenting a strategic alternative to traditional oil production methods. The work provides a comprehensive overview of the current research progress in the biosynthesis and biomanufacturing of microbial oils and vegetable oils. It highlights the commercial demonstration cases of microbial synthesis for high-value oils, including arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). It also presents the industrial demonstration cases of bulk oil synthesis, such as biorefining technology that utilizes lignocellulosic materials. The economic differences between vegetable oils and microbial oils are analyzed, emphasizing the challenges and opportunities in cost reduction and scalability. Additionally, the review summarizes the technologies for oil separation, extraction, and detection, which are critical for improving the efficiency and quality of oil production. Looking ahead, high-value oils are expected to undergo rapid development in the short term, driven by their applications in health, nutrition, and specialty chemicals. In the medium to long term, microbial bulk oils hold great potential, especially through the utilization of non-food feedstocks such as lignocellulosic biomass and industrial waste, enabling the transition to a circular economy in the oil industry. The integration of synthetic biology tools, including genetic engineering, metabolic pathway optimization, and high-throughput screening, will be essential for constructing efficient microbial cell factories capable of producing oils with high yields and tailored compositions. Furthermore, the development of low-cost, full-chain biorefining technologies will be crucial for overcoming the economic barriers to large-scale microbial oil production. By addressing these challenges, microbial oils have the potential to revolutionize traditional oil production methods, offering sustainable and environmentally friendly alternatives to meet the increasing global demand for oils. This review underscores the importance of continued research and innovation in synthetic biology and biomanufacturing to unlock the full potential of microbial and plant oils in various industrial applications. Table and Figures | Reference | Related Articles | Metrics

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Price to Cost-of-raw-materials Ratio (PC) of biomanufacturing: definition and application ZHANG Yi-Heng P. Job, CHEN Xuemei, SHI Ting Synthetic Biology Journal    2025, 6 (1): 8-17.   DOI: 10.12211/2096-8280.2024-072 Abstract （1374）   HTML （138）    PDF（pc） （3064KB）（979）       Knowledge map    Save Biomanufacturing is one of the strategic emerging industries in China during the “14th Five-Year Plan” period. The author once proposed “Tao-Fa-Shu-Qi” for the industrial biomanufacturing and provided its philosophical guideline. Focusing on the “Fa” of biological manufacturing and further analyzing the concept of “Fa as rules” in biomanufacturing, the author first proposed the concept of “Price to Cost-of-raw-materials Ratio” (PC value), which is the ratio of product market price to cost with raw materials. Biomanufactured products can be categorized by PC value into high-value products, value-added products, biocommodity, and products for public good. The PC value is a key indicator for evaluating the technological capability and economic viability of biomanufactured products. It is simple, transparent, and publicly accessible, offering a new approach for categorizing biomanufactured products. This indicator aids in guiding new technologies towards pathways of efficiency enhancement and cost reduction, forecasting future manufacturing costs and market prices for bioproducts, and assessing the industrialization potential of emerging biotechnologies. This article focuses on the biomanufacturing of fructose syrup, fructose solution, crystalline fructose, allulose, myo-inositol, and tagatose as examples, analyzing pathways for developing new technologies and predicting their economic feasibility. The calculation and analysis of the PC value could provide a new methodological tool for the top-level strategic design of the future development of emerging biomanufacturing industries, and could effectively facilitate the high-quality development of the bioeconomy. Table and Figures | Reference | Related Articles | Metrics

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Enabling technology for the biosynthesis of cosmetic raw materials with Saccharomyces cerevisiae ZUO Yimeng, ZHANG Jiaojiao, LIAN Jiazhang Synthetic Biology Journal    2025, 6 (2): 233-253.   DOI: 10.12211/2096-8280.2024-070 Abstract （1373）   HTML （186）    PDF（pc） （2379KB）（2085）       Knowledge map    Save With the rapid growth of consumption in cosmetics, demand for their raw materials is expanding correspondingly, which not only drive the efficacy and product competitiveness but are also crucial for ensuring safety. Synthetic biology, an emerging interdisciplinary field based on engineering principles, leverages gene editing, computer simulation, and bioengineering technologies to design, modify, and even resynthesize organisms through rational strategies. Saccharomyces cerevisiae, an important microbial platform, is increasingly used in the production of cosmetic raw materials. Constructing S. cerevisiae cell factories for the heterologous biosynthesis of cosmetic ingredients presents an eco-friendly and sustainable alternative to traditional plant extraction and chemical synthesis, addressing both environmental concern and resource limitation. In this article, we review the development of gene editing technology and its key role in constructing biosynthetic pathways for the production of cosmetic raw materials with S. cerevisiae. We also summarize the application of metabolic engineering strategies such as multi-copy gene integration, compartmentalization, transporter engineering, and multicellular system in the optimization of S. cerevisiae cell factories. Moreover, we present the latest progress in the biosynthesis of different cosmetic active ingredients with S. cerevisiae cell factories, such as terpenes, vitamins, polyphenols, proteins and amino acids. While the potential and advantages of using S. cerevisiae for large-scale production of cosmetic raw materials are significant, a series of challenges remain, including incomplete biosynthetic pathway analysis, low biosynthesis yield, and low yield with the separation and purification. Looking ahead, the integration of artificial intelligence, machine learning, and other advanced technologies is expected to establish more efficient gene editing tools for the optimization of yeast cell factories and the biosynthesis of cosmetic raw materials, providing technical support and practical guidance for the sustainable development of the cosmetics industry. Table and Figures | Reference | Related Articles | Metrics

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Research advances in nitrogen fixation synthetic biology LI Chao, ZHANG Huan, YANG Jun, WANG Ertao Synthetic Biology Journal    2025, 6 (5): 1041-1057.   DOI: 10.12211/2096-8280.2025-081 Abstract （1362）   HTML （64）    PDF（pc） （1881KB）（763）       Knowledge map    Save Nitrogen is an essential element for plant growth and development. Legume plants form symbiotic relationships with rhizobia, which facilitates the biological fixation of atmospheric nitrogen (N2) into ammonia (NH3) that is directly usable by the plants through the action of rhizobial nitrogenase. This process reduces the need for chemical nitrogen fertilizers. However, under the pressure of continuously increasing food demand driven by a growing global population, the major non-leguminous food crops for humans, such as maize, rice and wheat, lack the ability to form nodules and establish symbiosis with rhizobia. This results in a heavy dependence on chemical nitrogen fertilizer to maintain high and stable yields. However, the overuse of chemical nitrogen fertilizers has caused serious environmental problems, including soil compaction and acidification, greenhouse gas emissions, and water eutrophication, all of which threaten agricultural sustainability and global food security. To achieve green and sustainable agricultural development and reduce the use of chemical fertilizers, nitrogen-fixing synthetic biology utilizes tools of synthetic biology to modify, optimize, and even de novo design biological nitrogen fixation systems. These engineered systems are applied across agricultural production, environmental protection, and industrial biotechnology, addressing global challenges such as excessive dependence on chemical nitrogen fertilizers, high energy consumption, and environmental pollution. The innovative strategies for bioengineering biological nitrogen fixation in non-leguminous crops can be categorized into the following four aspects. These strategies include engineering rhizobial nitrogen-fixing bacteria to increase nitrogen supply to the host, engineering crops to enhance the ability of plants to recruit nitrogen-fixing microbes in the rhizosphere to improve nitrogen use efficiency, forming nodule-like structures for symbiotic nitrogen fixation, and transferring functional nitrogenase components into plant cells to create self-fertilizing crops. Significant advances have been achieved in all these approaches in recent years, demonstrating their potential to boost yields while reducing fertilizers. This review provides a comprehensive overview of recent breakthroughs in nitrogen-fixing synthetic biology. We also discuss the current challenges and future prospects, offering theoretical insights and technical guidance to support further research and the practical application of biological nitrogen fixation in sustainable agriculture and environmental protection. Table and Figures | Reference | Related Articles | Metrics

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Progress in the miniaturization of CRISPR-Cas systems DONG Ying, MA Mengdan, HUANG Weiren Synthetic Biology Journal    2025, 6 (1): 105-117.   DOI: 10.12211/2096-8280.2023-068 Abstract （1340）   HTML （95）    PDF（pc） （1409KB）（1311）       Knowledge map    Save The CRISPR-Cas gene editing technology has revolutionized the fields of biology, medicine, agronomy, etc. due to its simplicity and efficiency. Laboratory-developed tools, such as the widely recognized CRISPR-Cas9, have played a pivotal role in addressing a multitude of genetic diseases. By harnessing the targeted nucleic acid capabilities of the CRISPR-Cas system, researchers have successfully integrated various functionalities into Cas proteins, including fluorescent markers, transcriptional regulatory proteins, and base editing components. This has unlocked new possibilities, including chromosome imaging, transcriptional regulation, and precise base editing. Currently, Cas nucleases with large molecular weights, often exceeding 1000 amino acids, are commonly used. However, adeno-associated virus (AAV) vectors, which are extensively employed in gene therapy, have limited capacity to accommodate additional functional components beyond the coding sequences of CRISPR nucleases and guide RNAs (gRNAs). This limitation severely constrains their utilization in gene therapy and other applications. As a result, a significant focus of research has been placed on the miniaturization of CRISPR tools, making them compact enough to align with current delivery methods. Compact Cas protein variants within CRISPR-Cas systems hold the potential to create and deliver genome editing and regulatory tools into human cells using AAV. Hence, the development of miniaturized CRISPR-Cas systems presents a crucial avenue for addressing this technical challenge. This article provides a comprehensive review of research progress in miniaturizing key proteins within two classes of Cas systems: Cas9 and Cas12 for targeting DNA, and Cas13 for targeting RNA. This review encompasses the screening of novel Cas proteins, the reduction of protein structural domains, and the modification of guide RNAs, all with the intention of presenting innovative ideas for the further advancement of compact, precise gene editing, and regulatory tools. The miniaturization of CRISPR-Cas systems is a critical step toward unlocking their full potential in various fields, including biomedicine, agriculture, and basic research. As researchers continue to explore and refine these compact gene editing and regulatory tools, we can expect significant advancement in understanding and manipulating genetic information. This ongoing progress promises to have a profound impact on the future of science and technology. At present, the limitations of the miniaturized CRISPR-Cas system are mainly with the size of protein molecular weight and the efficiency and specificity of gene editing. If we can solve these problems and obtain a smaller structure in future research, not only can we optimize the transmission of the system in the body, but also develop high-efficiency and low-damage treatment methods for clinic applications. Table and Figures | Reference | Related Articles | Metrics