ABSTRACT The direct synthesis of high‐valence metal–organic frameworks (HV‐MOFs) under biocompatible conditions remains an outstanding challenge due to the strong Lewis acidity and sluggish coordination kinetics of their metal centers. Here, we report a mild, aqueous synthesis of UiO‐66—a benchmark Zr 4 + ‐based framework—using the conventional benzene dicarboxylic acid (H 2 BDC) linker. The approach enables the formation of highly crystalline protein@UiO‐66 composites while preserving biomolecule integrity and activity. In situ SAXS and cryoEM reveal that protein incorporation modulates prenucleation and growth dynamics, providing mechanistic insight into how the Lewis acidity of Zr 4 + governs framework assembly and biomolecule confinement. This work establishes a direct, biocompatible route to UiO‐66 and elucidates fundamental principles underlying MOF–biomolecule co‐assembly in highly Lewis‐acidic systems, advancing the design of robust biointegrated hybrid materials.
Díaz et al. (Sat,) studied this question.