Tunable Lipid–Corona Interfaces Enable Orientation-Controlled Antibody Immobilization and Enhanced Biofunctionality on Gold Nanoparticles

Antibody–nanoparticle conjugates underpin a wide spectrum of biomedical technologies, including targeted drug delivery, diagnostics, biosensing, and immunotherapy. However, their full potential is constrained by fundamental interfacial challenges, such as uncontrolled antibody adsorption, random orientation, and structural denaturation that compromise antigen-binding activity and colloidal stability. Conventional gold nanoparticle (AuNP) systems often suffer from aggregation, poor reproducibility, and loss of biofunctionality, limiting their translation into reliable therapeutic and diagnostic tools. Here, we introduce a strategy that protects AuNPs with a lipid corona, creating a biocompatible, tunable, and charge-regulated nanobiointerface that enhances their stability and functional performance. Our findings reveal that the lipid corona significantly improves the stability of AuNPs, facilitates antibody adsorption, and promotes favorable antibody orientation, while the AuNPs without lipid coating undergo aggregation. By tuning the base lipid composition, bilayer charge, and cholesterol content in lipid corona formation around AuNPs, this approach enables controlled antibody adsorption and promotes orientation by enhancing antigen-binding activity.