Enhancing Biocatalysis: Metal-Organic Frameworks as Multifunctional Enzyme Hosts.

Enzymes are highly efficient and selective catalysts that operate under mild conditions, making them invaluable for various chemical transformations. However, their limitations, such as instability and high cost, call for advancements in enzyme immobilization and the development of suitable host materials. Metal-organic frameworks (MOFs), characterized by high porosity, crystallinity, and tunability, are promising candidates for enzyme encapsulation. Among these, zirconium-based MOFs (Zr-MOFs) stand out due to their exceptional structural diversity and chemical stability. The physical and chemical properties of Zr-MOFs can be tuned and characterized with atomic precision, and their interactions with enzymes can be analyzed through a range of techniques spanning from chemistry and materials science to biochemistry. This tunable platform provides opportunities to systematically investigate the impact of encapsulation on the stability and activity of enzymes in order to develop design rules for enzyme hosts. In this Account, we discuss experimentally validated concepts for designing MOF hosts based on their structural properties and enzyme encapsulation mechanisms. We present methods to enhance enzyme catalytic performance through encapsulation and strategies for creating multifunctional enzyme@MOF systems via host modifications. We start by highlighting the importance of host structural design that maximizes substrate diffusion and enzyme availability, with particular focus on MOFs containing hierarchical mesoporous structures such as those in the topology. We then delve into the encapsulation process and host-guest interactions examined through techniques such as microscopy, calorimetry, and computational methods, which provide guidelines to fine-tune the local pore chemical environment to enhance enzyme stability and catalytic activity. Techniques found in biochemistry, such as isothermal titration calorimetry (ITC) and confocal laser scanning microscopy (CLSM), were developed to investigate enzyme encapsulation mechanisms, revealing high-entropy-driven host-guest affinity. Additionally, we discuss cases in which enzyme@MOF systems demonstrated enhanced catalytic activities and multifunctional capabilities. Encapsulated enzymes have demonstrated improved thermal and chemical stabilities compared to their free counterparts, maintaining activity under conditions that typically lead to denaturation. Additionally, the highly tunable nature of the MOF platforms allows them to support more complex systems such as tandem reactions, enabling applications in biophotocatalysis, bioelectrocatalysis, and targeted therapeutic protein delivery. The versatility of enzyme@MOFs promises extensive applications in both research and industrial processes across fields including biotechnology, pharmaceutical development, and environmental science. We provide an outlook for promising directions for enzyme@MOF research, with the aim of continuing innovation and exploration. We hope that this Account can benefit chemists, biologists, and material scientists toward designing efficient and adaptable next-generation biocatalytic composite materials.