Polyol-Mediated Suppression of Paddlewheel Hydrolysis Enables Biomimetic Mineralization of Unstable Metal–Organic Frameworks

Abstract Hydrolytically unstable metal–organic frameworks (MOFs) remain difficult to synthesize under aqueous, biocompatible conditions, limiting their integration with biomacromolecules. Here, we report a polyol-assisted aqueous strategy for the synthesis of highly crystalline HKUST-1 with tunable particle size under mild conditions. Polyols act as cosolvents that promote framework formation while enabling precise control over particle size through modulation of precursor concentration. Combined experimental studies and density functional theory calculations reveal that polyols stabilize the Cu(II) paddlewheel secondary building units against water-mediated hydrolysis, thereby enabling crystalline HKUST-1 formation in water. Importantly, these synthetic conditions are fully compatible with in situ protein encapsulation. Proteins spanning a broad range of electrostatic properties were successfully incorporated, yielding protein@HKUST-1 biocomposites that preserve structural integrity and retain enzymatic activity over multiple catalytic cycles. This work establishes a practical strategy for stabilizing hydrolytically unstable MOFs during aqueous synthesis, and broadens their integration with biomacromolecules for biotechnological and biomedical applications.