Lipoprotein-Driven Remodeling of Interfacial Charge Governs Protein-Mediated Implant Integration

Abstract Hyperlipidemia compromises implant integration, but the molecular mechanisms linking dyslipidemic environments to the biomaterial performance remain largely unknown. Here, we identify interfacial charge remodeling as a key regulator of the protein-mediated cell adhesion. Fibronectin (FN) is shown to govern endothelial attachment under hyperlipidemic conditions through charge-dependent interactions with the material surfaces. Molecular dynamics simulations reveal that the local charge distribution governs FN adsorption and conformational stability, while total internal reflection fluorescence (TIRF) single-molecule tracking demonstrates that charged adhesion domains regulate FN residence and adhesion stability in lipoprotein-rich environments. Deletion of negatively charged residues stabilizes FN–surface interactions, attenuates lipid-dependent disruption of adhesion signaling, and enhances endothelial responses. Similar charge-dependent behavior is observed on poly(lactic acid) (PLA), extending this interfacial charge remodeling from inorganic to organic biomaterials. These findings establish interfacial charge as a molecular determinant of implant integration under hyperlipidemic conditions and provide a general strategy for designing metabolism-responsive biomaterials.