A Solid‐State Crystallization Strategy for Direct Enzyme Encapsulation in Zr‐MOFs: Eliminating Harsh pH and Thermal Requirements of Liquid‐Phase Synthesis

Conventional syntheses of robust Zr-based metal-organic frameworks (Zr-MOFs) rely on harsh solvothermal conditions, precluding the inclusion of fragile functionalities such as enzymes or organisms. Therefore, developing routes to such stable frameworks under ambient conditions remains a significant challenge. Here, we report a mild aqueous solid-state crystallization (SSC) strategy that enables Zr-MOF assembly at ambient temperature. This approach transforms an amorphous precursor into a crystalline framework via water-mediated dynamic ligand exchange. Solid-state ¹³C NMR spectroscopy and density functional theory calculations reveal an acid-catalyzed associative substitution mechanism at Zr₆ nodes, in which formate modulators are protonated and displaced by fumarate linkers, driving MOF-801 crystallization without external heating or organic solvent. We further apply this SSC method to other Zr-MOFs, including functionalized UiO-66 analogues, establishing it as a general model for ambient MOF assembly. This amorphous-to-crystalline transformation represents a new synthetic paradigm for constructing stable porous frameworks under biocompatible conditions and enables the integration of sensitive biomolecules (e.g., enzymes) into robust MOFs. In addition, this method for MOF-801 formation is universally adaptable for encapsulating various proteins. The enzyme@Zr-MOF composites significantly enhance enzyme stability in catalytic reactions involving acidic products, demonstrating the necessity of robust Zr-MOF shells.