Palygorskite-based antibacterial composites induced intracellular S. aureus ferroptosis through SSTR2

Intracellular bacterial infections are paid more and more attention in clinic since there are no efficient antibiotics can be applied so far. It is well known that ZnO nanoparticles have excellent antibacterial properties, but high cytotoxicity limits their clinical application. As a natural one-dimensional nanomaterial, palygorskite (Pal) is an excellent carrier of ions and drugs due to its special crystal structure. The Pal-carried ZnO (ZnO@Pal) not only enhances its antibacterial properties, but also reduces the cytotoxicity. Our research group has successfully prepared ZnO@Pal-based antibacterial composites (Pal-ACPs) in the early stage, and confirmed that Pal-ACPs have excellent antibacterial performance. Moreover, a recent study has reported that ferroptotic stress promotes macrophages against intracellular bacteria. Whether Pal-ACPs can promote ferroptosis signaling in macrophages and lead to death of intracellular S. aureus remains largely unknown. In this study, we elucidated the mechanism of antibacterial effect of Pal-ACPs upon intracellular S. aureus and demonstrated that Pal-ACPs induced S. aureus undergoing ferroptosis in macrophages through SSTR2, and SSTR2 knockout prevented Pal-ACPs-induced ferrous iron accumulating in the bacteria, thus promote the survival of S. aureus in macrophages. Collectively, our new Pal-ACPs exhibit remarkably antibacterial potential and bear great prospects to be applied in clinical infectious disease therapy.