Biomaterial surface-induced immunoglobulin G unfolding enhances phagocytosis of Staphylococcus Aureus by macrophages

Implant-associated infections pose a significant clinical challenge, particularly in light of the growing threat of antibiotic resistance. Modulating host immune responses presents a promising alternative to traditional antimicrobial strategies. Herein, we investigate for the first time the contribution of biomaterial-induced IgG conformational changes to macrophage activation and bacterial clearance. To evaluate the influence of surface chemistry on IgG adsorption and immune system activation, we engineered four model surfaces via plasma polymerization, each with a distinct chemical composition rich in carboxylic acid, oxazoline, amine, and hydrocarbon functionalities. IgG adsorption and structural unfolding were evaluated using circular dichroism spectroscopy and synchrotron-based ATR-FTIR. Macrophage activation, including reactive oxygen species (ROS) production, extracellular trap (MET) formation, and phagocytosis, was assessed through confocal microscopy, scanning electron microscopy, and bacterial co-culture assays with S. aureus. Surfaces rich in oxazoline and amine groups induced significant IgG unfolding, enhancing macrophage adhesion, phagocytosis, ROS generation, and MET release. These immunomodulatory effects significantly increased macrophage phagocytic activity and decreased bacterial colonization, resulting in a reduction in S. aureus burden of up to 52 % compared to untreated controls. Our findings demonstrate that surface-driven IgG unfolding can serve as an effective mechanism for amplifying macrophage function and enhancing bacterial clearance. These findings reveal a previously unrecognized mechanism by which IgG structural changes at biomaterial interfaces instruct macrophage immune responses, offering a new strategy for engineering immune-instructive surfaces for infection-resistant implants. STATEMENT OF SIGNIFICANCE: Implant-associated infections pose a persistent clinical challenge, especially in the context of rising antibiotic resistance. Traditional antimicrobial strategies often fail to address the root causes of biomaterial colonization. This study uncovers a previously uncharacterized immunomodulatory mechanism whereby surface-induced immunoglobulin G (IgG) unfolding at the biomaterial interface significantly enhances macrophage activation, phagocytosis, reactive oxygen species generation, and macrophage extracellular trap formation. Using plasma-polymerized model surfaces with distinct chemistries, the research demonstrates that oxazoline and amine-rich surfaces promote IgG conformational changes that amplify macrophage responses, leading to a 52 % reduction in S. aureus burden. These findings reveal a previously unrecognized pathway by which protein conformational dynamics at biomaterial surfaces can instruct innate immune function. This work provides a blueprint for designing immune-instructive, infection-resistant implants. It introduces surface-driven IgG remodeling as a powerful strategy to harness and direct host immunity for next-generation medical devices.