Emerging Species and Genome Editing Tools: Future Prospects in Cyanobacterial Synthetic Biology
Open accessAbstract
Recent advances in synthetic biology and an emerging algal biotechnology market have spurred a prolific increase in the availability of molecular tools for cyanobacterial research. Nevertheless, work to date has focused primarily on only a small subset of model species, which arguably limits fundamental discovery and applied research towards wider commercialisation. Here, we review the requirements for uptake of new strains, including several recently characterised fast-growing species and promising non-model species. Furthermore, we discuss the potential applications of new techniques available for transformation, genetic engineering and regulation, including an up-to-date appraisal of current Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein (CRISPR/Cas) and CRISPR interference (CRISPRi) research in cyanobacteria. We also provide an overview of several exciting molecular tools that could be ported to cyanobacteria for more advanced metabolic engineering approaches (e.g., genetic circuit design). Lastly, we introduce a forthcoming mutant library for the model species Synechocystis sp. PCC 6803 that promises to provide a further powerful resource for the cyanobacterial research community.
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The most extensively studied unicellular cyanobacterial strains are Synechocystis sp. PCC 6803, Synechococcus elongatus PCC 7942, Synechococcus sp. PCC 7002, and the most studied filamentous cyanobacterium is Anabaena sp. PCC 7120.
“Most extensively studied unicellular cyanobacterial strains are Synechocystis sp. PCC 6803, Synechococcus elongatus PCC 7942, Synechococcus sp. PCC 7002, and the most studied filamentous cyanobacterium is Anabaena sp. PCC 7120 [20].”
From Cyanobacteria as a Photosynthetic Chassis for Metabolic Pathway Engineering with Heterologous Gene Expression (2026) · cites this paper as [20]
The Introduction identifies Synechocystis sp. PCC 6803 and Synechococcus elongatus PCC 7942 as model cyanobacteria. Section 2.1 discusses research using PCC 7002, and Section 3.1 identifies Nostoc (Anabaena) PCC 7120 as a filamentous strain used in genome-editing studies. The paper does not establish that these are the most extensively studied unicellular strains or that PCC 7120 is the most studied filamentous strain. (LLM, conf=0.84)
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Self-citationEngineering of a green‐light inducible gene expression system in S ynechocystis sp. PCC 6803
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“However, GSMs have only been developed for a small number of these, primarily models such as PCC 6803 [42], PCC 7942 [41] and more recently, UTEX 2973 [43] (Table 5).”
BackgroundProgress of CRISPR‐Cas Based Genome Editing in Photosynthetic Microbes
Naduthodi, M. I. S., Barbosa, M. J., & John van der, O. O. S. T. (2018) · Biotechnology Journal · doi:10.1002/biot.201700591 · Cited by 63 · cited 1× · see citing works
“We will not cover the specific mechanisms of all the available CRISPR/Cas tools here (for reviews, see [94,96]).”
MethodThermosynechococcus as a thermophilic photosynthetic microbial cell factory for CO2 utilisation
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“PKUAC-SCTE542 1), 2), 3), 6) Naturally transformable Spectinomycn BG-11 [82]”
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“CRISPR/Cas was first applied as a genome editing tool in 2012 [196] but only exploited in cyanobacteria in 2016 and then established for genome modification in several cyanobacterial species [18].”
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“More recently, strains capable of doubling in 2 h have been developed [8], which indicate that under favorable conditions, photosynthetic microorganisms are capable of growth rates similar to those of heterotrophs.”
BackgroundSEVA-Cpf1, a CRISPR-Cas12a vector for genome editing in cyanobacteria
Baldanta, S., Guevara, G., & Navarro-Llorens, J. M. (2022) · Microbial Cell Factories · doi:10.1186/s12934-022-01830-4 · Cited by 42 · see citing works
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Function and benefits of natural competence in cyanobacteria: from ecology to targeted manipulation
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“Several inducible promoter systems have been characterised in cyanobacteria [110–112] and multiple types of genome editing tools have been developed (recently reviewed in [113]).”
BackgroundTriassi, A. J., Fields, B. D., Monahan, C. E., Means, J., Park, Y., Doosthosseini, H., Padmakumar, J. P., Isabella, V. M., & Voigt, C. A. (2023) · Cell Systems · doi:10.1016/j.cels.2023.05.004 · Cited by 29 · see citing works
A toolbox to engineer the highly productive cyanobacterium <i>Synechococcus</i> sp. PCC 11901
Victoria, A. J., Selão, T. T., Moreno-Cabezuelo, J. Á., Mills, L. A., Gale, G. A. R., Lea-Smith, D. J., & McCormick, A. J. (2024) · Plant Physiology · doi:10.1093/plphys/kiae261 · Cited by 28 · see citing works
Self-citationLea‐Smith, D. J., Mills, L. A., Moreno-Cabezuelo, J. Á., Wlodarczyk, A., Victoria, A. J., Mejı́as, R., Nenninger, A., Moxon, S., Bombelli, P., Selão, T. T., et al. (2022) · Biomolecules · doi:10.3390/biom12070872 · Cited by 27 · see citing works
“Currently, there are five to seven antibiotic resistance cassettes which have been successfully used in model cyanobacterial species [40].”
BackgroundSelf-citationSynthetic biology approaches to copper remediation: bioleaching, accumulation and recycling
Giachino, A., Focarelli, F., Marles‐Wright, J., & Waldron, K. J. (2020) · FEMS Microbiology Ecology · doi:10.1093/femsec/fiaa249 · Cited by 27 · see citing works
Exploiting Polyploidy for Markerless and Plasmid-Free Genome Engineering in Cyanobacteria
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Exploring cyanobacterial diversity for sustainable biotechnology
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Cyanobacteria and Soil Restoration: Bridging Molecular Insights with Practical Solutions
García, M., Bruna, P., Durán, P., & Abanto, M. (2025) · Microorganisms · doi:10.3390/microorganisms13071468 · Cited by 15 · see citing works
“By localizing RuBisCO within carboxysomes, cyanobacteria significantly improve its catalytic efficiency compared to terrestrial plants [27,28].”
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Synthetic Biology in Cyanobacteria and Applications for Biotechnology
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Current knowledge on cyanobacterial biobutanol production: advances, challenges, and prospects
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Wannemaeker, L. D., Bervoets, I., & Mey, M. D. (2022) · Biotechnology Advances · doi:10.1016/j.biotechadv.2022.108028 · Cited by 11 · see citing works
Applications of phage-derived RNA-based technologies in synthetic biology
Zhang, W., & Wu, Q. (2020) · Synthetic and Systems Biotechnology · doi:10.1016/j.synbio.2020.09.003 · Cited by 10 · see citing works
“coli to the cell that has difficulty in genome editing like cyanobacteria [190].”
Madsen, M. A., Hamilton, G. M., Herzyk, P., & Anna Amtmann, A. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.619055 · Cited by 10 · see citing works
“For example, the phycocyanin promoters (Pcpc) of Synechocystis sp. PCC 6803 and PCC 6714 have been used to drive heterologous expression in Synechococcus sp. PCC 7002 and PCC 7942 (Markley et al., 2015; Gao et al., 2016).”
BackgroundThe Molecular Toolset and Techniques Required to Build Cyanobacterial Cell Factories
Opel, F., Axmann, I. M., & Klähn, S. (2022) · Advances in Biochemical Engineering/Biotechnology · doi:10.1007/10_2022_210 · Cited by 7 · see citing works
Optogenetic control of gene expression in the cyanobacterium Synechococcus sp. PCC 7002
Forbes, L., Papanatsiou, M., Palombo, A., Christie, J. M., & Anna Amtmann, A. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1529022 · Cited by 5 · see citing works
A green microbe for a sustainable future: the versatile applications of Nostoc commune
Onyeaka, H., Akinsemolu, A., Muhammad, A. I., & Ejiohuo, O. (2025) · Sustainable Microbiology · doi:10.1093/sumbio/qvaf025 · Cited by 5 · see citing works
Interfacing solar energy with bacterial metabolism for sustainable chemical synthesis
Trotter, C. L., Clouston, K., Steele, J. F. C., Marlow, L., & Wallace, S. C. (2026) · Nature Reviews Clean Technology · doi:10.1038/s44359-025-00141-2 · Cited by 5 · see citing works
“For example, the completion of CyanoSource will give cyanobacterial researchers a library of gene knockout strains for phenotyping and bioengineering 310,311 , analogous to the E. coli KEIO strains that have been available for almost two decades 312 .”
Lindberg, P., Kenkel, A., & Bühler, K. (2023) · Advances in biochemical engineering, biotechnology · doi:10.1007/10_2023_217 · Cited by 5 · see citing works
Antimicrobial activity of Cyanobacteria-derived compounds
Gómez-Espinoza, O., Núñez-Montero, K., & Barrientos, L. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-821491-6.00006-5 · Cited by 5 · see citing works
Biotechnological Applications of Cyanobacteria: Synechocystis and Synechococcus Strains
Bolay, P., Toepel, J., & Bühler, B. (2025) · Advances in biochemical engineering, biotechnology · doi:10.1007/10_2025_282 · Cited by 4 · see citing works
Tiwari, D., Kumar, N., Bongirwar, R., & Shukla, P. (2024) · World Journal of Microbiology and Biotechnology · doi:10.1007/s11274-024-04064-1 · Cited by 3 · see citing works
“CyanoSource barcoded mutant library for the model species Syn6803 (Gale et al. 2019) contains a collection of knock-out strains with gene deletions, making it approachable for researchers to understand the gene functions.”
SEVA-Cpf1, a CRISPR-Cas12a vector for Genome Editing in CyanobacteriaPreprint
Baldanta, S., Guevara, G., & Lloréns, J. M. N. (2022) · Research Square · doi:10.21203/rs.3.rs-1411584/v1 · Cited by 3 · see citing works
Engineering the highly productive cyanobacterium Synechococcus sp. PCC 11901Preprint
Victoria, A. J., Selão, T. T., Moreno-Cabezuelo, J. Á., Mills, L. A., Gale, G. A. R., Lea‐Smith, D. J., & McCormick, A. J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.04.552009 · Cited by 3 · see citing works
“coli ‘helper’ strain with 185 appropriate transmissible plasmids to enable conjugation of mobilizable plasmid vectors, 186 such as RSF1010-based vectors (Gale et al., 2019).”
BackgroundMethodInfluentialSelf-citationFlaherty, D., Hoefnagel, I., Hogervorst, P. A. M., & Klaassen, P. (2025) · Sustainability & Circularity NOW · doi:10.1055/a-2540-9377 · Cited by 2 · see citing works
“Thus, effective governance of such transitions requires a mature understanding of societal perceptions [26, 45], policies and governance [46], economics and sustainability [12], technological developments [47], and how all these interact.”
Harnessing engineered cyanobacteria for next-generation therapeutics
Bhardwaj, A., & Mishra, A. K. (2026) · Archives of Microbiology · doi:10.1007/s00203-026-04790-0 · Cited by 2 · see citing works
“…chassis, Synechococcus elongatus UTEX 2973 has emerged as a promising heterologous host owing to its rapid doubling time and environmental robustness (Gale et al. 2019). deletion, or replacement of genes at defined loci (Zhang et al. 2021), facilitating direct rewiring of metabolic pathways.”
Paduvetnaya, L., Venkatesh, K. H., & Madhyastha, H. (2024) · Energy, environment, and sustainability · doi:10.1007/978-981-97-1152-9_19 · Cited by 2 · see citing works
Zhang, H., Chen, P., Russel, M., Tang, J., Jin, P. K., & Daroch, M. (2021) · Plants · doi:10.3390/plants10081540 · Cited by 2 · see citing works
Walshe, J., & Saha, S. K. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48060638 · Cited by 1 · see citing works
“Most extensively studied unicellular cyanobacterial strains are Synechocystis sp. PCC 6803, Synechococcus elongatus PCC 7942, Synechococcus sp. PCC 7002, and the most studied filamentous cyanobacterium is Anabaena sp. PCC 7120 [20].”
Temperature-induced zeaxanthin overproduction in Synechococcus elongatus PCC 7942
Casazza, A. P., Lombardi, A., Menin, B., & Santabarbara, S. (2022) · Photochemical & Photobiological Sciences · doi:10.1007/s43630-022-00352-7 · Cited by 1 · see citing works
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“The precise identification of these key genes pro - vides a crucial foundation for employing genetic engineering techniques to enhance the production of scytonemin and MAAs in cyanobacteria (Gale et al. 2019; Govindasamy et al. 2022).”
Mangrove cyanobacterial diversity as a source of bioactive natural products
Roy, A. R., Basu, S., Villalobos, S. D. L. S., & Mukherjee, J. (2026) · Current Research in Microbial Sciences · doi:10.1016/j.crmicr.2026.100557 · Cited by 1 · see citing works
“Genome-scale metabolic models (GSMs) now support both systems biology and biotechnological engineering in cyanobacteria (Goodall et al., 2018; Gale et al., 2019).”
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Additional file 3 of SEVA-Cpf1, a CRISPR-Cas12a vector for genome editing in cyanobacteria
Baldanta, S., Guevara, G., & Navarro-Llorens, J. M. (2022) · Figshare · doi:10.6084/m9.figshare.19921035
Nagy, C. I., Thiel, K., Mulaku, E., Mustila, H., Tamagnini, P., Aro, E.-M., Pacheco, C. C., & Kallio, P. T. (2021) · Figshare · doi:10.6084/m9.figshare.14954556
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- Authors
- Gale, G. A. R., Schiavon Osorio, A. A., Mills, L. A., Wang, B., Lea-Smith, D. J., & McCormick, A. J.
- Affiliations
- University of Edinburgh (GB)
- Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK
- University of East Anglia (GB)
- School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK
- Corresponding author
- McCormick, Alistair J.
- Venue
- Microorganisms
- Publisher
- MDPI AG
- Published
- 2019-09-29
- Volume
- 7
- Issue
- 10
- Pages
- 409
- ISSN
- 2076-2607 (ISSN-L)
- PMC
- PMC6843473
- OpenAlex
- W2977031274
- Cited by
- 61
- References
- 264
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 13 · 2021: 14 · 2020: 8 · 2019: 1 · 2018: 1
- FWCI
- 0.79
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Microorganisms (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- UK Research and Innovation (MR/S018875/1)
- Consejo Nacional de Ciencia y Tecnología
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/M010996/1, BB/R506527/1, BB/S020128/1, M010996, 1802017, M010996/1, BB/S507404/1, BB/S020365/1, BB/N007212/1, BB/S020365)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Algal biology and biofuel production
- Keywords
- cyanobacteria, synthetic biology, genome editing, CRISPR-Cas, CRISPR interference, non-model organisms, Synechocystis sp. PCC 6803, mutant library, genetic circuit design, metabolic engineering, algal biotechnology
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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