Mechanistic Understanding of Protein–MOF Integration through Surfactant-Driven Interfacial Design

Integration of proteins into metal–organic frameworks (Protein@MOF) represents an effective method for protein stabilization, with rising demand across material and biomedical sciences. However, the molecular mechanism of protein–MOF interactions remains unsettled due to challenges in developing a general platform to systematically investigate such interactions, hindering improvements in their chemical and physical properties. Here, we develop a surfactant-guided strategy to modulate the assembly of protein@MOF through interfacial design. We discovered that the interfacial environment between proteins and MOFs is the primary factor determining encapsulation efficiency, structural retention, and functional performance. Lipid-based non-ionic surfactants such as glycerol monooleate (GMO) increase the protein’s solvent-accessible surface area (SASA), suggesting partial remodeling of the protein surface and hydration shell. GMO at the interface of protein@MOF results in a 20% improvement in protein encapsulation and a 30% increase in MOF growth rate. All-atom molecular dynamics simulations reveal domain-specific interactions between GMO and flexible surface residues on protein in a concentration-dependent manner, involving both electrostatic and hydrophobic contacts. This work offers new molecular insights into how surfactant-driven interfacial design fine-tunes the stability of protein@MOF, laying the foundation for robust alternatives to lipid nanodiscs for membrane protein stabilization, and protein-based platforms for drug-delivery, biocatalysis, and biosensing.