Enzyme‐Assisted Confined Synthesis of Metal Nanoparticles in Covalent Organic Frameworks for Efficient Enzyme‐Metal Cascade Catalysis

The integration of enzymatic and metal catalysis in cascade reactions offers a highly efficient approach for producing high-value chemicals, such as chiral pharmaceuticals. However, overcoming the inherent incompatibility between metal and enzyme catalysts and optimizing their stability and activity to achieve effective synergy, remains a significant challenge. Here, we present an enzyme-assisted, confined synthesis of metal nanoparticles (MNPs) within the nanochannels of covalent organic frameworks (COFs), to construct efficient enzyme-metal hybrid catalysts for cascade reactions. The COF nanochannels stabilize the enzyme during MNP formation and the catalytic process, and synergize with the enzyme to regulate the size, dispersion, and electronic state of the MNPs through surface amino acid residues, realizing the co-encapsulation and dual-optimization of both components. Using Candida antarctica lipase B (CALB) and Pd nanoparticles as a model system, Pd/CALB@COF exhibits an 8.2-fold higher yield in the kinetic resolution (KR) of racemic 1-phenylethylamine (1-PEA), and a 2.7-fold enhancement in racemization conversion, compared to counterparts without COF. Their synergy in dynamic kinetic resolution (DKR) delivers 91% yield, >98% enantiomeric excess (e.e.) value, and recyclability, with applicability to various chiral amines. This strategy has been validated across different metal-enzyme systems, establishing a versatile platform for designing efficient enzyme-metal cascade systems.