Co‐Confinement of Enzymes and Cofactors Within Pickering Droplet Derived Microreactors for Continuous Flow Catalysis

ABSTRACT The co‐immobilization of enzymes and cofactors represents a sustainable platform for continuous‐flow synthesis of chiral pharmaceuticals, yet balancing effective retention with mutual accessibility of them remains challenging. Herein, we report a sol‐gel strategy to construct Pickering droplet derived microreactors (PDMRs) for the co‐confinement of enzymes and cofactors, which have been applied to continuous flow reactions without exogenous addition of cofactors. Within these self‐sufficient PDMRs, the cofactors are reversibly immobilized via electrostatic interactions, enabling in situ regeneration and free access to the enzyme. The PDMRs efficiently encapsulate enzymes and cofactors with 85–100% immobilization efficiency and robust thermal stability. In PDMRs‐catalyzed continuous flow reactions, excellent catalytic performance and high cofactor total turnover number (TTN) were obtained in nicotinamide adenine dinucleotide phosphate (NADP + )‐dependent aldo‐keto reductase (AKR) catalyzed enantioselective reductions (80–100% conversions, >99% ee, 500 h stability, up to 173 907 mol mol −1 TTN), and pyridoxal 5‐phosphate (PLP)‐dependent transaminase (TA) catalyzed enantioselective transaminations (80–100% conversions, >99% ee, 2 000 h stability, up to 45 552 mol mol −1 TTN). Furthermore, the PDMRs are extended to the co‐confinement of a multi‐enzyme system (AKR and glucose dehydrogenase, GDH) with NADP + for chiral alcohols synthesis with sustained operational stability. This work establishes a potent and durable strategy for industrial‐scale continuous flow manufacturing.