Advancing synthetic biology for sustainable one-carbon biomanufacturing

Synthetic biology presents a promising pathway for transforming abundant one-carbon (C1) compounds, such as CO₂, methane, and methanol, into value-added products using engineered microbes, providing a sustainable alternative to conventional biomanufacturing methods without competing with food resources. Despite the growing use of C1 feedstocks as supplementary carbon sources, their use as sole carbon substrates remains challenging because of inefficient enzyme kinetics, metabolic imbalances, and incompatibility between heterologous pathways and host physiology. This review presents recent progress in the engineering of natural and synthetic microbial chassis, focusing on the dual role of rational design and artificial intelligence (AI) in aligning exogenous C1-assimilating modules with endogenous metabolic networks. We propose that overcoming these bottlenecks requires system-level integration of multi-omics-guided strain optimization, AI-assisted protein engineering, and dynamic pathway regulation. By bridging foundational discoveries with scalable applications, this review provides a reference for the development of scalable and sustainable microbial platforms for the high-value conversion of C1 compounds, ultimately contributing to carbon neutrality and the mitigation of climate change.