Regulating xenophagy and phenotype of macrophages by selenium-doped nanoleaves on Zn-based implants for infected bone integration.

Abstract

Implant-related osteomyelitis presents a significant clinical challenge, characterized by bacterial invasion, aggressive inflammation, and impaired osteogenesis. Zn-based implants are biodegradable and bacteriostatic, showing great potential for bone repair, however, the excessive release of Zn²⁺ ions induces cytotoxicity and impacts early bone formation. To overcome this limitation, biomimetic selenium-doped Ca₅(PO₄)₂SiO₄ nanoleaves (Se-CPS) were fabricated on Zn-1Ca (ZN) substrate. Se-CPS not only moderates the degradation of ZN, maintaining Zn²⁺ release within a biocompatible range, but also sustainably supplies therapeutic ions (Se, Ca, Si, P) and establishes an alkaline microenvironment. When bacteria invade, the combined action of Zn²⁺ ions and alkalinity eliminates 75-88% of bacteria by generating abundant intracellular reactive oxygen species (ROS), and concurrently, macrophages clear residual bacteria through enhanced xenophagy, a process driven by regulating the key autophagy-related genes (LC3-I/LC3-II, p62, Beclin 1, FLT4 and ATG5). Following bacterial eradication, antioxidative function of Se-CPS-mediated by the upregulation of selenoprotein genes (GPx1, GPx3, GPx4, TrxR1, SEPSH1, DIO1) restores cell viability and promotes the polarization of macrophages from the pro-inflammatory M1 to the pro-healing M2 phenotype. The combined antibacterial, immunomodulating, and osteogenic effects of Se-CPS were further validated in an osteomyelitis model, demonstrating enhanced osteointegration. This work presents an effective surface engineering strategy for Zn-based implants, enabling simultaneous infection control, inflammation modulation, and accelerated biointegration in an osteomyelitis microenvironment.