Beyond nature: charting the roadmap to intelligent biomanufacturing for sustainable biohydrogen

Hydrogen has been recognized as a key pillar of future energy systems in the global pursuit of carbon neutrality. However, hydrogen production processes still highly rely on fossil fuels. Biohydrogen production is a microbial-based process that converts biomass, organic waste, and solar energy into hydrogen via dark fermentation, photo-fermentation, or photolytic water-splitting pathways. It is a promising pathway to sustainable energy, with the potential for carbon-negative emissions under favorable feedstock and system-boundary conditions. Yet, the limitations of natural biological systems, such as poor energy conversion efficiency, huge carbon diversion, and poor operational robustness, have prevented its transition from laboratory research to industrial application. To resolve these bottlenecks, this review proposes a strategic shift from traditional biological conversion toward intelligent biomanufacturing via three enabling technologies: (1) synthetic biology to design microbial cell factories with a tailored hydrogen-centric metabolism; (2) nanomaterials engineering to create smart biotic-abiotic interfaces for overcoming the physical limitations of electron and mass transfer; and (3) artificial intelligence to enable autonomous bioprocessing through predictive digital twins and self-optimizing reactor systems. These three pillars can bridge molecular-scale engineering to system-level intelligence. A scalable roadmap starting from modular bioreactor design, waste-derived feedstock integration, and rigorous techno-economic and life-cycle assessment has been outlined to position biohydrogen within circular economy and potentially carbon-negative ecosystems. This review suggests a pathway to make biohydrogen an important, efficient, cost-effective, and reliable building block of the future hydrogen economy.