A Supramolecular Approach to Engineering Living Cells with Enzymes for Adaptive and Recyclable Cascade Synthesis

Abstract

Biocatalytic transformation in nature is inherently dynamic, spontaneous, and adaptive, enabling complex chemical synthesis and metabolism. These processes often involve supramolecular recognition among cells, enzymes, and biomacromolecules, far surpassing the capabilities of isolated cells and enzymes used in industrial synthesis. Inspired by nature, here we design a supramolecular approach to equip living cells with these capacities, enabling recyclable, efficient cascade reactions. Our two‐step "plug‐and‐play" methodology begins by coating Escherichia coli cells with guest‐containing polymers (SupraBAC) via supramolecular charge interactions, followed by the introduction of β‐cyclodextrin‐functionalized host enzymes through host‐guest chemistry, creating a robust cell‐enzyme complex. This supramolecular coating not only protects cells from various stresses, such as UV radiation, heat, and organic solvents, but also facilitates the overexpression of intracellular enzymes and the attachment of extracellular enzymes within and on SupraBAC. This combination results in efficient multienzyme cascade synthesis, enabling two‐ and three‐step reactions in one pot. Importantly, the multienzyme system can be recycled up to five times without significant loss of activity. Our findings introduce a versatile, adaptive supramolecular coating for whole‐cell catalysts, offering a sustainable and efficient solution for complex synthesis in both chemistry and industrial biotechnology.