Formate as a feedstock for single-cell protein production: Candidate formatotrophs, fermentation challenges, and scalability

With a rising population, the demand for proteins containing a high-quality essential amino acid profile is increasing. Traditional agricultural practices are threatened by climate change, suggesting that innovative food and feed production methods are required to strengthen global food security. Formate is a potentially renewable substrate that can be assimilated into single-cell protein by formatotrophs, which use formate as the sole carbon and energy source for growth. Furthermore, formate possesses a myriad of technical advantages over alternative one‑carbon compounds that may accelerate scale-up. This review aims to provide a state-of-the-art overview of single-cell protein production using formate as a fermentation feedstock. Analysis of native formatotrophs including Cupriavidus necator and Methylorubrum extorquens suggests that they can produce biomass with favourable nutritional profiles for food and aquafeed applications. However, key challenges persist. These include a high biomass RNA content, the presence of endotoxins, and low growth rates and biomass yields. The impact of these challenges for food and feed applications is discussed, as are the emerging strategies to overcome them. Particularly, optimised fermentation feeding and adaptive laboratory evolution, which can improve the fermentation performance without the need for genetic engineering, are explored. Furthermore, we examined the potential of CO₂-based formate for single-cell protein production and proposed an integrated process. Overall, this review summaries current research progress for formate-based single-cell protein production and highlights the priority areas for future research required to achieve industrial scale-up.