From laboratory to industry: Systematic approaches to the biomanufacturing of short-chain diols.
Short-chain diols (C2-C6) are key platform chemicals widely used in polyesters and polyurethanes; however, their large-scale adoption remains limited by cost, scalability, and process robustness. This review summarizes recent advances in microbial production from an integrated perspective encompassing chassis engineering, pathway engineering, and process optimization. We compare model and non-model hosts, highlighting trade-offs between genetic tractability and native metabolic capacity, and analyze biosynthetic pathways with respect to carbon efficiency, redox balance, and pathway compatibility. Strategies to enhance microbial cell factories including enzyme engineering, metabolic flux regulation, cofactor engineering, and adaptive laboratory evolution are discussed to improve titer, yield, and productivity. We further evaluate the shift toward low-cost and sustainable feedstocks, such as crude glycerol, lignocellulosic biomass, and C1 substrates. To bridge microbial production with industrial implementation, key industrial constraints, including oxygen transfer, feedstock variability, downstream separation and biosafety, are examined. A second-hydroxyl-forming-unit conservation rule is proposed and integrated with process-level evidence to assess structural, performance, and process transferability across diol pathways. Techno-economic analysis (TEA) and life-cycle assessment (LCA) are discussed as essential tools for evaluating industrial feasibility. Finally, the downstream value of short-chain diols beyond their conventional uses is discussed, with emphasis on emerging opportunities for bioconversion and catalytic upgrading into high-value chemicals and functional materials. These analyses provide an evidence-based framework for product-specific pathway and process decisions in short-chain diol biomanufacturing.