An Injectable Magneto-Responsive Periosteum Reprograms Neutrophil Extracellular Trap Formation for Osteomyelitis Treatment.

Abstract

Osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) biofilms presents significant therapeutic challenges due to antibiotic resistance and persistent bacterial presence. Inspired by the natural periosteum structure, we developed an injectable biomimetic periosteum through thiol-click chemistry-a hydrogel loaded with NiSr MOF@Mem nanocomposites(NiSr MOF@Mem Gel). This system not only serves as a physical barrier covering bone defects but also, under alternating magnetic field (MF) activation, synergistically executes chemodynamic therapy, controlled antibiotic release, and immunomodulation. In vitro studies demonstrated that this biomimetic periosteum activates NADPH oxidase-dependent ROS bursts under MF, driving PAD4-mediated histone H3 citrullination and thereby inducing neutrophil extracellular trap (NET) formation. This process relies on the classical ROS/PAD4 signaling axis, as confirmed by the PAD4 inhibitor Cl-Amidine significantly suppressing NETosis. Functional assays verified that the system, via NET induction, exerts potent synergistic antibacterial effects against both planktonic and biofilm-embedded MRSA. In a rat osteomyelitis model, the biomimetic periosteum combined with MF treatment significantly reduced bacterial load in bone tissue and effectively promoted bone repair by modulating the immune microenvironment. This study presents a novel strategy of using a magnetically responsive biomimetic periosteum to remotely regulate innate immunity for biofilm eradication, offering an integrated solution for the synergistic treatment of osteomyelitis.