A blueprint for designing the next-generation of synthetic C1 microbes

Engineering microbes for synthetic one-carbon (C₁) assimilation continues to gain momentum with the expanding demand for sustainable bioprocesses. While most efforts focused on model microbes, non-canonical hosts offer untapped potential due to native metabolic properties, enzyme activities, and substrate tolerance. This perspective outlines key considerations for selecting and engineering such strains, including metabolic modeling, use of native C₁-inducible promoters, and adaptation to anaerobic conditions. Environmental impacts are evaluated through life cycle assessment, identifying substrates with low carbon footprints. Integrating techno-economic and sustainability insights at early stages is essential to guide the development of efficient, scalable C₁-based biomanufacturing systems.