Enhanced Anti-Infective Efficacy of ZnO Nanoreservoirs through a Combination of Intrinsic Anti-Biofilm Activity and Reinforced Innate Defense

The increasing prevalence of implant-associated infections (IAIs) imposes a heavy burden on patients and medical providers. Bacterial biofilms are recalcitrant to antiseptic drugs and local immune defense and can attenuate host proinflammatory response to interfere with bacterial clearance. Zinc oxide nanoparticles (ZnO NPs) play a dual role in antibacterial and immunomodulatory activities but compromise the cytocompatibility because of their intracellular uptake. Here, ZnO NPs were immobilized on titanium to form homogeneous nanofilms (from discontinuous to continuous) through magnetron sputtering, and the possible antimicrobial activity and immunomodulatory effect of nano-ZnO films were investigated. Nano-ZnO films were found to prohibit sessile bacteria more than planktonic bacteria in vitro, and the antibacterial effect occurred in a dose-dependent manner. Using a novel mouse soft tissue IAI model, the in vivo results revealed that nano-ZnO films possessed outstanding antimicrobial efficacy, which could not be ascribed solely to the intrinsic anti-infective activity of nano-ZnO films observed in vitro. Macrophages and polymorphonuclear leukocytes (PMNs), two important factors in innate immune response, were cocultured with nano-ZnO and bacteria/lipopolysaccharide in vitro, and the nano-ZnO films could enhance the antimicrobial efficacy of macrophages and PMNs through promoting phagocytosis and secretion of inflammatory cytokines. This study provides insights into the anti-infective activity and mechanism of ZnO and consolidates the theoretical basis for future clinical applications of ZnO.