Chemo-Enzymatic Cascades for Integrated Lignocellulose Valorization: Catalyst Design, Compatibility Bottlenecks and Reactor Intensification

Efficient valorization of recalcitrant lignocellulosic biomass to platform chemicals and biofuels is needed for the transition to a circular bioeconomy. Conventional biorefineries are based on decoupled multi-step processes with energy penalties, interstage product loss, and product inhibition. Integrated chemo-enzymatic one-pot cascades constitute a paradigm shift in process intensification by combining biocatalytic selectivity with the fast kinetics of heterogeneous chemical catalysis. However, practical implementation is limited by compatibility bottlenecks such as different optimal temperatures, pH, solvent toxicity, and mutual deactivation of catalysts. This review critically examines recent advances in bridging these incompatible interfaces. We discuss catalyst design strategies centered on spatial compartmentalization within metal–organic frameworks (MOFs), mesoporous silica, magnetic nanocomposites, and Pickering emulsions. Furthermore, we examine solvent engineering using deep eutectic solvents and ionic liquids alongside continuous flow microfluidic and membrane bioreactors that overcome mass transfer limitations and product inhibition. Comparative benchmarking of synthetic routes for carbohydrate dehydration/hydrogenation and lignin oxidative depolymerization/funneling in terms of catalytic configurations, reaction modes and process performance is presented. Finally, techno-economic analyses and life cycle assessments indicate a potential 25–40% reduction in capital expenditure and over 70% net greenhouse gas savings. Future directions emphasize computational enzyme design and scalable flow reactor engineering to enable industrial translation.