Natural product is an important source of small-molecule drugs and probes, but its synthesis is challenging and has attracted lasting attention in the field of organic chemistry. With the continuous advancement of chromatographic techniques for separation and spectroscopic methods for structural analysis, the pace of discovering tiny bioactive natural products is accelerating, concomitantly leading to an increase in the diversity and complexity of the newly identified structures. However, to meet the demand of the quantity for the study of their structure-activity relationships, target identification, in vivo activity evaluation, etc., growing challenges in the requirement for the synthetic efficiency, economy, and scalability of natural products are emerging. Synthetic practices in a chemoenzymatic way have provided multi-dimensional visions for natural product research, which emerged as a hot research topic in recent years. On the one hand, enzymatic catalysis has provided highly efficient and selective synthetic methodologies that would complement traditional synthetic methods. On the other hand, the introduction of enzyme-catalyzed reactions would bring a new mode of strategic design for synthesis, enabling the rapid and diverse synthesis of natural products with high efficiency. In this context, how to integrate the enzyme-catalyzed reactions into the synthesis of natural products is the key to a successful chemoenzymatic synthesis. We herein summarized three roles played by the applications of enzyme-catalyzed reactions in the current practices of chemoenzymatic synthesis of natural products. ①The involvement of biocatalysis would introduce a chiral center or a key functional group into the starting material, or supply complex synthetic precursors (e.g., polysubstituted (hetero)aromatics, chiral pools, etc.) via in vitro enzyme-catalyzed reactions or fermentation, hence advancing the starting line of synthesis; ②Late-stage enzyme-catalyzed chemo-, regio-, and stereoselective modifications of substrates with heavily substituted functional groups or inert positions of complex skeletons; ③The strategic application of enzymatic catalysis as a key carbon-carbon bond-forming step in the construction of the skeleton of natural product. Finally, we have also discussed the current challenges and future trends of the chemoenzymatic synthesis of natural products in three facets, including the design of synthetic strategy, the development of synthetic methods, as well as persons involved in the research. Thus, the integration of interdisciplinary methods and technologies, including chemical synthesis and biocatalysis, would invigorate the synthesis of natural products.

Steroids exhibit a range of biological activities and are commonly described as the ‘key to life’ in nature. Steroidal-based medications have emerged as the second largest pharmaceutical category following antibiotics, owing to their remarkable bioactivities such as anti-infective, anti-inflammatory, anti-allergic, and antitumor properties. This category encompasses more than 400 drug compounds, representing approximately 17% of FDA-approved medications. The synthesis of steroidal products continues to attract significant attention due to their diverse bioactivities and physicochemical characteristics in pharmaceutical applications. With the increasing demand for steroidal drugs and the fluctuating availability of sapogenin resources, the use of Mycobacteria to convert inexpensive phytosterols to produce key intermediates for steroid drugs has been established as the most mature and sustainable industrial route. However, the complex structure of steroids, particularly their highly oxygenated skeleton, poses challenges for the well-established semi-synthesis route of complex steroid medications. Recent strides in bioinformatics and genetics have significantly advanced the studies on synthesis of steroidal compounds. This review highlights recent advancements in the synthesis of high-value steroids, including the diverse steroid drug intermediate production via external steroidal modifying enzymes expression in engineered Mycobacteria, chemo-enzymatic synthesis of complex steroids, and yeast-based de novo synthesis. It specifically highlights the significant achievements in the chemo-enzymatic synthesis, which combines the precise site- and stereoselectivity of enzymatic transformations with the efficiency of chemosynthesis, enabling the concise synthesis of complex steroidal products. Recent advancements in chemoenzymatic strategies, especially those involving P450 hydroxylase, 3-sterone-Δ¹-dehydrogenase, reductase, and enzyme cascades, have significantly contributed to the efficient and straightforward synthesis of complex steroid medications. On this basis, the future research opportunities and challenges are also discussed, aiming to provide a reference for the efficient development of more value-added steroid compounds, including the development of new generation steroid intermediates, the discovery of novel steroid biocatalysts, and the establishment of steroid synthesis pathways in mycobacteria.

Although bioactive natural products have played significant roles in pharmaceutical research, their application potential is still limited by low isolated yields and structural modification challenges. To overcome these obstacles, developing environmentally friendly and highly efficient synthetic strategies offers exceptional approaches to obtain complex bioactive natural products and their analogs. Driven by advancements in microbial genetics and enzyme engineering, chemoenzymatic strategies, which merge enzymatic and synthetic transformations, are steadily emerging as potent tools in the synthesis of bioactive natural products, pharmaceutical components and other valuable molecules. These fashionable strategies offer not only advantages of chemical synthesis, such as simplicity, flexibility and scalability, but also those of biosynthesis, including environmental friendliness, high selectivity and efficiency. This will establish a linkage into the next-generation synthesis which is expected to break the boundary between chemistry and biology. Versatile cytochrome monooxygenases, P450s, can achieve inert C—H bond selective oxidation in mild and green conditions, a classically challenging organic transformation, providing novel retrosynthetic plans for complex natural products and becoming one of the hotspots in synthetic science. This review summarizes the recent applications of chemoenzymatic synthesis of natural products using P450-catalyzed site-selective oxidations as critical steps to improve the synthetic efficiency and avoid unnecessary functional group transformations and protection/deprotection steps, categorizing the case studies by structure features, such as steroids, terpenoids, and other types of natural products. At the end of this review, the current challenges in this field, such as heavily relying on the native activities of enzymes, are also analyzed and discussed, along with emerging research directions and technologies in new enzyme mining and enzyme engineering that may provide solutions to these challenges in the future. With constantly cross fusion of biosynthesis, chemical synthesis, synthetic biology, protein engineering, machine learning and other research field, P450-catalyzed site-selective oxidations will be becoming routine tools for synthetic chemists.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of peptide natural products that often contain noncanonical amino acids and structural motifs with promising potential as drug leads. One unique structural unit found in RiPPs is the C-terminal S-[(Z)-2-aminoethenyl]-D-cysteine (AviCys) or (2S,3S)-S-[(Z)-2-aminoethenyl]-3-methyl-D-cysteine (AviMeCys). Avi(Me)Cys-containing RiPPs usually exhibit potent antimicrobial or anticancer activities, which strictly require the presence of the C-terminal AviCys motifs. Despite the potential of Avi(Me)Cys-containing RiPPs as drug leads, lack of synthetic methods and biosynthetic systems to access these type of cyclic peptides impede the application of Avi(Me)Cys-containing peptides in medicinal chemistry. In this review, we summarize the current understanding of the biosynthesis of Avi(Me)Cys-containing peptides and the progress made in the development of chemical methods to synthesize Avi(Me)Cys motifs and derivatives. This review contains two following major sections: ① The biosynthetic process of Avi(Me)Cys motifs in the different families of Avi(Me)Cys-containing RiPPs, including lanthipeptides, lipolanthines, linaridins and thioamitides, are introduced with three essential enzymatic steps: first, a cysteine decarboxylase oxidatively decarboxylated the C-terminal cysteine, generating a highly reactive enethiol; subsequently, distinct enzymes catalyze the dehydration of a serine/threonine (Ser/Thr) residue or the dethiolation of a Cys residue in the precursor peptide by incorporating a dehydroalanine (Dha) or dehydrobutyrine (Dhb) residue; finally, a putative cyclase catalyzes the Michael-type addition between the enethiol group and a Dha/Dhb residue to yield the Avi(Me)Cys motif. Detailed enzymatic investigation of these biosynthetic steps are introduced. ② The chemical synthesis of the Avi(Me)Cys building block and their analogues via diverse synthetic methodology, including the radical thiol-yne coupling, the oxidative decarboxylation/decarbonylation, and the condensation of amides with acetals. Overall, further elucidation of the complete biosynthetic pathway for Avi(Me)Cys motifs in related RiPPs, along with advancements in the chemical synthesis of Avi(Me)Cys-containing natural product peptides, will facilitate the effective utilization of these bioactive peptide natural products.

Photocatalysis has the advantages of mild reaction conditions, renewability, and strong reactivity, but the poor selectivity limits its further application in asymmetric synthesis. Enzymatic catalysis shows unique advantages of high selectivity and specificity, but it leads to some defects such as limited reaction types and relatively narrow substrate scope. Photoenzymatic catalysis combines the advantages of high reactivity of photocatalysis with high selectivity of enzymatic catalysis, providing a novel synthesis model, that is more in line with the requirements of modern green organic synthesis. The term “photoenzyme reactions” narrowly refers to the synergistic catalysis involving photoenzymes, which can be classified into the following four categories: natural photoenzymactic reactions, artificial photoenzymatic reactions, photo-biocatalysis cascade reactions, and photo-induced promiscuous enzymatic reactions. However, natural photoenzymes are rarely found in nature, the stringent substrate scope further hinders their application. Artificial photoenzymes integrate photosensitizers into the scaffold of natural enzymes, which have been well summarized in previous reviews. Photo-biocatalysis cascade reactions by combining photochemical steps and enzymatic steps can realize some complex organic synthesis processes. Since the first report on NAD(P)H-dependent KREDs-catalyzed enantioselective radical dehalogenation of lactones, photosensitive cofactor-dependent unnatural photoenzymatic catalysis demonstrated its great potential in the field of organic synthesis, and continues to thrive to date, which has addressed many problems difficult to be achieved in traditional organic synthesis. Since 2023, research into the promiscuity of photoenzyme catalysis has witnessed continuous breakthroughs, reporting diverse novel types of photoenzyme catalytic reactions and mechanisms. The precise control over stereoselectivity and even regioselectivity directly addresses the longstanding challenges in the field of organic synthesis. While there have been many publications summarizing the related research, yet rarely focused on this rapidly evolving field. In this review, we summarize the recent and representative reports of photo-induced promiscuous enzymatic reactions, and classify them according to asymmetric dehalogenation, hydrogenation, intramolecular cyclization, intermolecular C—C/C—N/C—S cross-coupling reactions through free radical pathways, etc. These reactions exhibit different mechanisms due to different enzymes and substrates. For example, in the process of redox initiation, there are two types: single-electron reduction initiation and single-electron oxidation initiation. In the radical termination process, single-electron reduction termination and single-electron oxidation termination may be used. The diversity of mechanisms also makes it possible to develop more photoenzyme-catalyzed promiscuous reactions. In the future, new photoenzymatic methods will be promoted by rapidly developing technologies such as genetic engineering, synthetic biology, enzyme engineering, flow chemistry, and artificial intelligence, and more efficient and highly selective new-to-nature reactions will emerge, significantly expanding the application range of photoenzyme catalysis in the field of green asymmetric synthesis.

Stereochemical control is an important long-standing research topic in synthetic chemistry. Enzymes, as green and highly selective natural chiral catalysts, face constrains in synthetic applications due to their evolution-defined molecular structure and catalytic mechanism. Photocatalysis represents an important strategy to initiate free radical reactions by capturing photon energy to activate the chemical bonds of substrate molecules. As an emerging synthetic tool for asymmetric synthesis, photobiocatalysis merges the advantages of photochemistry and enzyme. Unfortunately, photoenzymes are rather rare in nature. Thus far photoenzymes identified are DNA photolyases, light-dependent protochlorophyllide reductases and blue light-responsive algal photodecarboxylases. Utilization of advanced molecular biotechnologies such as protein engineering and directed evolution under the guidance of chemical mechanisms of photocatalysis enables us to explore unknown photocatalytic functions of natural coenzymes, synergize photocatalysts and enzymes, and rationally design artificial photoenzyme with defined functions. The past few years have witnessed remarkable advances in these aspects, significantly surpassing the spectrum of substrates and reactions of enzyme catalysis, compensating for the scarcity of natural photo-enzymes and expanding the chemical boundaries and synthetic space of biocatalysis. This review summarizes the latest research progress in chemically-driven photoenzymatic asymmetric reactions. Based on their merging modes, the review categorizes the integration of light and enzyme into four classes: coupling of exogenous photocatalysts and native enzymes, photobiocatalysis driven by excitation of electron donor-acceptor complex, direct photoredox catalysis by coenzymes, and energy transfer photobiocatalysis. The chemical mechanism of bond activation by photocatalysis and synergistic control of stereoselectivity by enzyme in these photobiocatalytic systems are discussed in detail. In the end of this review, we also delineate the present challenges of asymmetric photobiocatalysis including the monotonicity of native photoactive cofactors and low catalytic efficiency for abiological reactions. This review also proposes future directions from the perspectives of new natural enzyme mining, expansion of artificial photoenzymes, enzyme de novo design, and whole-cell catalysis, which are anticipated to foster green bio-manufacturing of high-value functional molecules through the fusion of chemistry and biology and push forward the sustainable development of synthetic chemistry.

Terpenoids are a class of natural products with important physiological functions and significant biological activities that are widely found in nature and have a wide range of applications in the food, medical, and daily chemical industries. In the biosynthetic pathway of terpenoids, terpene synthases often determine the type and novelty of the terpene carbon skeleton, and tailoring enzymes, such as cytochrome P450 enzymes, can carry out a variety of post-modifications, ultimately resulting in terpenoids with a rich diversity of structures and functions. In recent years, with the development of genome-sequencing technology and synthetic biology, a large number of terpene biosynthetic enzymes of plant and microbial origin have been characterized, which, excitingly, include non-canonical terpene synthases that can also catalyze the generation of unique cyclized skeletons. Meanwhile, the use of combinatorial biosynthetic strategies has led to the creation of many novel and unnatural terpenoids, further enriching the kingdom of terpenoids. Here, we review the recent advances in non-canonical terpene cyclases and combinatorial biosynthetic pathways over the past five years, with a view to shedding light on the discovery and biosynthesis of novel terpenes in the future. Firstly, the newly discovered novel enzymes with terpene cyclization functions are reviewed, containing a new subclass of type Ⅰ terpene synthases, non-squalene triterpene synthases, UbiA-type terpene cyclases, cytochrome P450 oxygenases, methyltransferases, vanadium-dependent haloperoxidases, and haloacid dehalogenase, along with their sequences, functions, and possible cyclization mechanisms, which can contribute to our understanding of terpenoid biosynthetic enzymes and the discovery of novel terpenoids. This review then describes the combinatorial biosynthesis of non-canonical terpenoids. By combining terpene synthases with methyltransferases or natural/artificial cytochrome P450 oxygenases, a series of unnatural terpenoids containing non-canonical C₁₁ and C₁₆ backbones, or with unusual structural modifications, were produced. This could inspire the structural innovation studies of terpenoids in the future. The discovery of novel enzymes and the construction of novel combinatorial biosynthetic pathways will further broaden the structural diversity and chemical space of terpenoids, which is expected to provide more potential novel terpenoids for clinical drug development.

Glycosylation modifications, extensively present on the surfaces of eukaryotic proteins as a type of post-translational modification, hold significant physiological and pathological implications. The microscopic heterogeneity of natural glycoproteins has led to the emergence of the chemical synthesis of homogeneous glycoproteins with defined structures as a crucial frontier in exploring the structure-function relationships of glycosylation modifications. With the flourishing development of protein synthesis and glycoengineering technologies, various protein ligation and polysaccharide synthesis strategies have been developed, enabling the preparation of glycoproteins containing hundreds of amino acid residues. The development of glycoprotein synthesis strategies primarily revolves around chemical and enzymatic approaches for glycosidic bond formation, leading to effective synthesis schemes such as Lansbury’s aspartic acid acylation, chemical strategies based on glycosyl amino acid building blocks, and glycan remodeling strategies using endoglycosidases and glycosyltransferases. This review will discuss the chemical and enzymatic construction of glycosidic bonds, examining existing strategies for the total synthesis of glycoproteins and semi-synthetic approaches that combine with biological expression methods. It will introduce these strategies’ achievements in synthesizing complex homogeneous glycoproteins with different types of glycosylation modifications, such as those with multiple complex N-glycosylation modifications like HSV gD and those containing long hydrophobic segments like IL-2. Additionally, this review will highlight breakthroughs in understanding the structure-function relationships of glycosylation modifications in various physiological processes through these synthetic complex glycoproteins, including the relationship between glycan chain length and immunogenicity in antigenic glycoproteins, and the mechanisms by which O-GlcNAc regulates synaptic function in neurons. Finally, it will summarize the progress made in glycosidic bond construction, purification strategies, and protein solubility, and point out that further optimization of selectivity and synthetic yield remains a pressing issue in the field of glycoprotein synthesis. The wide application of glycoprotein synthesis technology in developing immunotherapies and understanding the molecular mechanisms of various diseases expands the development directions of synthetic science in the field of life and health, from understanding principles to developing products.

DNA-Encoded Library (DEL) technology, as an emerging means of small molecule drug screening, has become an important and indispensable technology platform for new drug discovery and development. The technology incorporates many advantages from combinatorial chemistry, molecular biology, and chemical bioinformatics, which greatly improve the efficiency of compound library synthesis and screening. Meanwhile, driven by the development of nucleic acid-compatible chemical reactions and high-throughput sequencing technology, DEL technology has made remarkable progress and gradually become a fast, economical, and efficient high-throughput screening platform, and has been more and more widely used in seedling compounds screening by universities, research institutes, and large pharmaceutical companies. The success of a DEL screening relies heavily on the chemical space and structural diversity of the compound libraries, both of which are directly affected by the number of chemical reactions compatible with nucleic acids. Therefore, developing the on-DNA chemical reactions to continuously enrich the chemical toolbox for DEL synthesis and thus enhance the structural diversity and drug potential of the molecules in the libraries has been the focus in this field. In recent years, the number of on-DNA chemical reactions has increased significantly, greatly broadening the scope of chemical reactions available for DEL construction. Meanwhile, a series of novel reaction methods, such as photocatalysis, electrocatalysis, and biosynthesis, have also emerged in the application of on-DNA chemical reactions and further expanded the field that on-DNA chemical reactions can reach. In this paper, we systematically review the metal-catalyzed on-DNA chemical reactions in recent years, including C(sp²)—C(sp²) bond-formation reactions, C(sp³)—C(sp³) bond-formation reactions, C(sp²)—C(sp³) bond-formation reactions, and C(sp²)—X bond-formation reactions; the synthesis of on-DNA privileged heterocycles with single-ring, fused-ring, and spirocyclic rings by using target-oriented synthetic and diversity-oriented synthetic strategies; the research progress of photocatalytic and enzyme-catalyzed on-DNA chemical reactions. However, the current developments in on-DNA reactions also have limitations, such as compatibility with nucleic acids and substrate suitability. In the future, it is important to exploit more robust on-DNA reactions that can proceed under mild conditions, new types of on-DNA reactions, and the combination of high-throughput screening and computer-assisted on-DNA reactions.

Advances in science and technology are creating huge benefits and value for society. The digitalization of the world has brought great changes to human being’s daily life. Meanwhile, the increasing degree of digitalization has led to an unprecedented explosion of data, resulting in increasingly severe information storage challenges. According to the current developing trend, the global data volume is expected to reach 175 zettabytes by 2025. With the rapid growth of global data volume and the exponential growth of total data, the existing storage methods will no longer be able to meet the storage needs brought by the digitalization of the world and then there is an urgent need to develop information storage methods with better storage performance, higher storage efficiency and more durable storage media. Nature has offered a powerful solution by using DNA molecules as carriers of information, where genetic information has been transferred stably more than a million years. DNA storage has many advantages over traditional storage media, including high storage density, potentially low maintenance costs, and ease of synthesis and chemical modification, which make it an ideal alternative for information storage. The current process of storing data in DNA includes six main steps: encoding, writing, preservation, retrieval, reading, and decoding. Among them, the writing of data is the basic for realizing the storage of data in DNA, concluding writing data in DNA sequence and in DNA structure. In this review, we first introduce strategies for in vivo data writing in DNA storage systems, which primarily involve writing data into DNA sequences and DNA structures. This is followed by an overview of the development of in vivo writing techniques in DNA storage systems. Finally, we discuss the challenges faced by DNA storage systems in terms of high writing costs and slow writing speeds, and prospects for large-scale synthesis of high-purity DNA and improved biocatalysts.

In order to achieve carbon neutrality and green economy, people use biorefinery technology to transform and utilize CO₂. Microbial electrosynthesis (MES) is an emerging technology that converts CO₂ into chemicals by electrically driven biocatalysts. Currently, the low efficiency of microbial carbon sequestration, an incomplete understanding of electron transfer mechanisms, low synthesis rate, and poor applicability of reactor components have been the limiting factors for the large-scale application of MES. In this paper, the mechanisms of electron supply in the MES system, including through electrodes and electron donors such as H₂, formic acid, CO, and other molecules, are systematically reviewed based on how cathodic microorganisms obtain electrons. It is an effective method to improve electron transport efficiency by modifying conductive nanowires of electroactive microorganisms and optimizing the expression of microbially associated hydrogenase, formate dehydrogenase and CO dehydrogenase using synthetic biology techniques. Additionally, cathode modification aimed at improving electron transfer rates between microbes and electrodes, enhancing the biocompatibility, and providing more reducing power can facilitate the generation of value-added products. In addition to enhancing the electron transfer efficiency of the cathode, the construction of a reactor with high efficiency of gas-liquid-solid mass transfer and electron transfer, the reduction of anode potential for water electrolysis, and the regulation of microbial activity are also important strategies to enhance MES performance. In the future, it is necessary to further elucidate the mechanism of microbial electron transport and strengthen the performance of MES by means of synthetic biological communities, and by designing a more efficient electrode interface that balances electron transfer rate, substrate mass transfer and biocompatibility. In terms of the scaling-up of reaction devices, electron transfer and gas mass transfer can be improved through the combination of various methods, and integrating product separation processes can promote the further development of the technology and provide new ideas for the realization of the “Carbon Peak and Carbon Neutrality” goal.

Organic acids, as important platform chemicals, have been widely used in food, pharmaceutical, chemical industries and agriculture. Currently, microbial production of organic acids relies primarily on sugars as feedstocks, which may suffer from the competition with food and arable lands. One carbon (C₁) molecules such as CO, CO₂, methane, methanol and formic acid are widespread and inexpensive, which are considered as ideal feedstocks for future bio-manufacturing. Bioconversion of C₁ feedstocks toward the production of organic acids helps mitigate greenhouse effect and realize carbon neutrality. Therefore C₁ sources have been regarded as raw materials of third generation biorefinery, and natural C₁ utilizing microbes attracted increasing attention. Although some microorganisms have native biosynthetic pathway of organic acids, the production efficiency is usually lower than expected. This review summarizes the recent progress on the biosynthesis of organic acids (3-hydroxypropionic acid, lactic acid and succinic acid) from C₁ feedstocks using synthetic biology methods. First, the native C₁ utilizing pathways are summarized, including CO₂, CO, methane, methanol and formic acid. Then the metabolic engineering strategies to improve organic acids production were systematically reviewed, including the optimization of rate-limiting enzymes expression, enhancement of the supply of precursor and cofactor, cofactor engineering, and inhibition of the product degradation. In addition, the challenges, solutions, and prospects of C₁ bioconversion to organic acids are also discussed, and coupling chemical catalysis and biological transformation may provide a promising industrial route for organic acids production. In particular, methanol is an ideal C₁ feedstock with many advantages like convenient storage and transportation, high liquid-to-liquid mass transfer efficiency, and it can also be massively produced from CO₂ by “liquid sunshine” technology. Therefore constructing high efficient methanol cell factory may enable organic acids production from CO₂, a carbon neutral production manner. This review may provide a guidance for C₁ biorefinery and industrial bioproduction of organic acids.

The extensive consumption of fossil oil and the rapid accumulation of greenhouse gas emissions have caused long-term changes in the global climate and environment, sparking widespread interest in society for CO₂ bioconversion technologies as a means to address energy transition and climate change. As a new-generation biorefinery platform based on synthetic biology, the synthetic phototrophic community comprises closely cooperating phototrophic and heterotrophic microorganisms. This community is capable of efficiently converting light energy directly into biomass and a variety of chemicals through mutualistic metabolic division of labor among community members. Synthetic phototrophic community is one of the potential ways to achieve sustainable carbon-negative biomanufacturing, and has attracted widespread attention attributed to its advantages in applicability and robustness. In recent years, with the rapid development of systems biology and synthetic biotechnology, a variety of research efforts have been applied to the design and optimization of synthetic phototrophic communities, achieving stable progress and promoting the understanding of phototrophic community production. In this review, we briefly introduced an overview of the advances and current status of synthetic phototrophic community, including mutualistic mechanisms related to element, energy, and information flow. Subsequently, the unique advantages of phototrophic community were outlined. Meanwhile, recent systems biology approaches of phototrophic community were summarized, such as integrative analysis of multi-omics data, genome-scale metabolic modelling, flux balance analysis and community performance predictive algorithms. We also focused on the design and optimization strategies, such as chassis upgrading, immobilization/compartmentalization techniques, and enhanced internal multilayer regulation of synthetic phototrophic community, as well as the progress of their applications in various fields. Furthermore, we analyzed and discussed the constraints and challenges for the further deployment of synthetic phototrophic community on a larger scale, ranging from photosynthetic carbon production rate, intermediate organic matter selection, external predator invasion, to light distribution under high density cultivation. Finally, the future research strategies and engineering directions of synthetic phototrophic community encompassing semiconductor biohybrids, fine regulation of interspecies interaction and multi-omics community model construction were proposed. We conclude by providing a perspective on the future application scenarios of synthetic phototrophic communities in biochemistry, biomedicine, bioremediation and bioagriculture.

Synthetic biology offers boundless possibilities and revolutionary changes to material fields. One remarkable outcome of interdisciplinary integration of synthetic biology and material science is the development of environmentally friendly polyhydroxyalkanoates (PHAs), which serve as ideal alternatives to petroleum-based plastics. PHAs are a family of linear biopolyesters synthesized by various microorganisms as their intracellular storage materials for energy and carbon sources. With at least 150 various monomers, PHAs exhibit diverse structures, material properties, and applications, collectively known as “PHAomics”. When reprograming microbial genomes via synthetic biology and metabolic engineering, in combination with the feeding of special precursors, tailor-made PHAs with defined structures and varied properties can be synthesized. PHAs has been extensively studied in both academia and industry in the last few decades, leading to the commercialization of some PHAs. Next generation industrial biotechnology (NGIB) based on halophilic Halomonas spp. as chassis has been developed to overcome the limitations of current industrial biotechnology. NGIB offers a long lasting, open and continuous, energy and freshwater-saving bioprocess using low-cost mixed substrates and allows morphology engineering for simplified downstream processing. NGIB facilitates low-cost production of various PHAs in large scale. This review introduces PHAomics and summarizes the diverse properties of PHAs produced via NGIB. It primarily focuses on the composition, structure, and material properties of PHAs, as well as their extensive applications in biodegradable plastics, medical implants, medicine, drug delivery carriers, energy sources, and potential smart materials. Additionally, it covers the strategies and tools for strain engineering and their achievements in the tailor-made biosynthesis of PHA using reprogrammed Pseudomonas spp. and Halomonas spp. Finally, this review discusses strategies on how to further reduce the production cost and improve material properties of PHAs. This review summarizes the progresses on the low-cost customized synthesis of PHA biomaterials by synthetic biology, demonstrating the integration of biology and chemistry.