Microbial engineering for the conversion of C1 feedstocks into value-added bioproducts: recent advances and perspectives.

Biomanufacturing advances sustainable production and circular economy, while wastes-derived one-carbon (C1) compounds (e.g., CO2, methanol, formate and methane) expand substrate diversity, accelerate wastes valorization, and mitigate climate change. The design of C1 feedstocks-driven biorefineries is often hindered by: limited genetic toolkits, impaired cell growth, inefficient substrate utilization, and unclear metabolic mechanism. In this context, this review addresses these challenges through comprehensive analysis of: pathway exploitation, metabolic regulation, emerging technology, and biochemicals synthesis for optimizing C1-trophic performance. We first analyze key bottlenecks in enhancing assimilation efficiency of natural C1-utilizers, and then systematically summarize the strategies for harnessing nontraditional feedstocks using: engineered autotrophs, methylotrophs, formatotrophs, and methanotrophs. Importantly, we outline a bottom-up framework on systematic and modular redesign of C1-driven microbial cell factories for promoting industrial applications. Finally, we identify unresolved challenges and strategic opportunities to guide environmental preservation and performance optimization. Overall, this review provides a roadmap for transformative progress in sustainable biomanufacturing and wastes re-utilization.