Ceramide, a fundamental bioactive molecule found ubiquitously in eukaryotic organisms, exerts profound regulatory effect on cellular physiology, encompassing critical roles in signaling cascades, cellular proliferation, differentiation, and apoptosis, as well as immunomodulation. In dermatology, ceramides play an indispensable role as constituents of the stratum corneum, the outermost layer of the skin, where they are crucial for maintaining the integrity of the epidermal barrier, regulating moisture retention, combating oxidative stress linked to aging, and exhibiting notable antimicrobial and anti-inflammatory properties. The multifaceted biological functions of ceramides underscore their extensive applications in various industries, including cosmetics, biomedicine, functional food, and animal nutrition, highlighting their significant market potential and therapeutic value. The chemical synthesis of ceramides poses substantial challenges due to the intricate stereochemistry involved, necessitating precise control over synthetic pathways. As a result, current commercial sources predominantly rely on semi-synthetic methods that integrate traditional natural extraction techniques with biochemical transformations of sphingolipid precursors to achieve targeted ceramide structures. Recent advancements in synthetic biology have explored microbial systems for the production of sphingolipids, including ceramides, offering promising avenues for scalable and sustainable synthesis. However, optimizing de novo synthesis pathways and their efficiency in microbial cell factories remains a primary research focus. Strategies aimed at enhancing ceramide yield and purity through metabolic engineering and pathway optimization are pivotal for advancing industrial applications. This paper provides a systematic review of the physiological effectiveness and function of ceramides, encompassing their physiological roles and various applications. It begins with an overview of ceramide extraction methods, including both natural extraction techniques and chemical synthesis approaches for ceramides and their precursor compounds. Subsequently, the review addresses the sphingolipid synthesis pathways and their associated key enzymes, detailing strategies for pathway regulation and optimization, as well as the aspects of product transport, storage, and secretion. Additionally, it explores the identification and expression of key enzymes. The paper concludes by examining future directions in the field, such as addressing aggregation toxicity in ceramide synthesis, enhancing transport and secretion mechanisms, advancing digital modifications of catalytic elements, and expanding gene regulatory target exploration. By synthesizing current knowledge and highlighting avenues for innovation, this review aims to catalyze further research effort toward achieving efficient ceramide production. Ultimately, optimizing ceramide synthesis has the potential to unlock its full potential in various sectors, contributing to its advancement in skincare, therapeutics, and functional materials. The integration of microbial systems is particularly promising for expanding production capabilities while addressing sustainability concerns in ceramide manufacturing. Continued advancements in synthetic biology and biotechnology are expected to revolutionize the landscape of ceramide applications, paving the way for enhanced therapeutic interventions and novel industrial applications in the future.

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.

Functional peptides are short chain peptides composed of 2 to 50 amino acids, and their biological activities are closely related to their amino acid sequences, chain length, and structural architectures. Functional peptides can play a regulatory role in a variety of physiological processes by specifically recognizing and binding to target molecules in vivo. Due to their rapid action, strong specificity, less side effect and toxicity, functional peptides have shown great application potentials in many fields such as biomedicine, food science and cosmetics. For example, in the field of biomedicine, functional peptides can be used as the basic material of antimicrobe, anticancer, immune regulation and other therapeutic factors. In the food industry, they are used as natural supplements to enhance nutritional value for health benefit. In the field of cosmetics, functional peptides are widely used for the anti-aging, moisturizing, and repairing of the skin. In this paper, we discuss the ways of obtaining functional peptides, mainly including protein hydrolysis, chemical synthesis, and biosynthesis (e.g., through microbial recombinant expression technology), and compare their advantages and disadvantages and respective application scenarios. In terms of strategies for mining functional peptides, we review the latest research progress including phage surface display, machine learning algorithm, molecular docking and artificial intelligence. These techniques show significant potentials in the screening and design of functional peptides. In recent years, the rapid development of synthetic biology and the wide applications of bioinformatics and artificial intelligence have provided new ideas and strategies for the discovery and optimization of functional peptides, making it possible to screen functional peptides through machine learning and high throughput. Looking forward to the future, the research of functional peptides will face new challenges and opportunities. Improving the synthesis process for high efficiency, improving the stability of functional peptides through structural modifications, and using computer-aided optimization and artificial intelligence to design multifunctional peptides will become important research directions. At the same time, strengthening the safety and efficacy assessment of functional peptides can further enhance the applications of functional peptides.

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”.

Non-renewable resources, such as petrochemicals, have made great contributions to modern civilization. However, the extensive use of fossil fuels, which have been buried for hundreds of millions of years, has led to a substantial increase in carbon imbalance. The imbalance leads to severe ecological and environmental problems. Industrial biomanufacturing, often referred to as a “sunshine economy”, represents a novel sustainable production paradigm, utilizing renewable resources in a carbon-cycling mode. This paper discusses several ways in which biomanufacturing can support China’s “carbon peaking and carbon neutrality” goals from the perspectives of manufacturing feedstock, production mode and product usage. Biomanufacturing can reduce carbon emissions through feedstock substitution, technology iteration and product replacement. Utilization of straw biomass, producing non-food proteins and establishing a biobased industry landscape are important approaches for reducing carbon emissions in biomanufacturing. Efficient biomanufacturing of food and natural products can substantially improve production efficiency, conserve significant land resources, and thus provide land resources for “carbon replacement”. Optimizing agricultural products through biotechnology advancements and innovative product development is a crucial way to reduce pollution but also enhance the carbon sink capacity of the agricultural sector.

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.

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.

Synthetic genetic circuits are engineered gene networks comprised of redesigned genetic parts for interacting to perform customized functions in cells. With the rapid development of synthetic biology, synthetic genetic circuits have shown significant application potentials in many fields such as biomanufacturing, healthcare and environmental monitoring. However, the efforts to scale up genetic circuits are hindered by the limited number of orthogonal parts, the difficulty of functionally composing large-scale circuits, and the poor predictability of circuit behaviors. A longstanding goal of synthetic biology research is to engineer complex synthetic biological circuits, using modular genetic parts, as we do with electronic circuits. Synthetic biologists have developed various genetic toolboxes and functional assembly methods over the past few decades. Here we present an overview of the latest advances, challenges, and future prospects in genetic circuit engineering from four aspects corresponding to the four key engineering principles for circuit design, i.e. orthogonality, standardization, modularity, and automation. Firstly, the design and construction of orthogonal genetic part libraries are discussed in both prokaryotes and eukaryotes at the levels of DNA replication, transcription, and translation, respectively. Standardized characterization methods and the design of modular genetic parts are subsequently summarized. Furthermore, progress in developing modular genetic circuits are presented, providing new concepts and ways for engineering increasingly large and complex circuits. Finally, how to achieve automated design and building of genetic circuits are addressed from the advances in software, hardware and artificial intelligence, respectively, with an aim to replacing the presently time-consuming manual trial-and-error mode with the iterative "design-build-test-learn" cycle for improved efficiency and predictability of circuit design. The integration of these fundamental principles and the latest advances in information technology such as artificial intelligence and lab automation will accelerate the paradigm shift in genetic circuit engineering and synthetic biology research, making it feasible for designing synthetic lives to meet various customized needs.

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.

Optogenetics represents an advanced technology that facilitates precise control of gene expression and neuronal activity in living cells through light. Introduced by neuroscientist K. Deisseroth in 2005, this methodology has transformed neuroscience research, empowering researchers to modulate excitable tissues and neural circuits with exceptional spatiotemporal accuracy. Optogenetics necessitates the expression of light-sensitive proteins, including channelrhodopsins, halorhodopsins, and various microbial opsins, within specific cells. Employing viral vectors and tissue-specific promoters, these proteins ensure targeted expression. Exposure to designated wavelengths of light permits these proteins to activate or inhibit cellular activity, thereby modulating neuronal behavior. The implementation of optogenetics has significantly enhanced comprehension of learning, memory, and neural plasticity. This technology enables the examination of the molecular dynamics associated with synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD), which are pivotal for memory. Real-time manipulating of specific neuronal populations can elucidate the intricate neural circuits involved in these phenomena. Additionally, optogenetics has facilitated the exploration of potential therapeutic approaches for neurological conditions such as Alzheimer’s disease by meticulously controlling memory-associated circuits. The utility of optogenetics transcends fundamental research, yielding promising prospects in addiction to studies and motor function enhancement. By modulating distinct neural circuits, it is possible to alter addiction-related behaviors and augment motor functions. Furthermore, the amalgamation of optogenetics with cutting-edge technologies like artificial intelligence and deep learning is anticipated to refine stimulation protocols, resulting in more precise and efficacious experimental outcomes. Notwithstanding its transformative capacity, the clinical application of optogenetics encounters significant obstacles, including the requisites for safe and effective gene delivery systems and the formulation of light-sensitive proteins with optimal characteristics for applications in human beings. Future investigations should concentrate on surmounting these hurdles while expanding the applications of optogenetics in neuroscience and related fields. The integration of optogenetics with multidisciplinary approaches is poised to unveil new realms in brain research, yielding profound insights into mechanisms governing memory, learning, and neural plasticity.