Sonocatalytic multifunctional hydrogel in-situ remodels the infectious microenvironment for eradicating refractory osteomyelitis.

Osteomyelitis remains a formidable clinical challenge due to biofilm-associated antibiotic resistance, a hypoxic and immunosuppressive microenvironment, and progressive inflammatory bone destruction. To address these multifactorial barriers, we developed an ultrasound (US)-activatable injectable hydrogel, designated MIL-101(Fe)@ZnO@MM + PFO + Gel, which integrates sonodynamic catalysis, oxygen regulation, and immunomodulation within a single therapeutic platform. The core-shell nanostructure comprises MIL-101(Fe)@ZnO nanoflowers, synthesized via a seed-mediated growth process to couple the redox activity of iron with the peroxidase-like catalytic properties of ZnO. The core-shell nanostructure comprises MIL-101(Fe)@ZnO nanoflowers, synthesized via a seed-mediated growth process to couple the redox activity of iron with the peroxidase-like catalytic properties of ZnO. These nanozymes are camouflaged with a thiolated macrophage membrane (MM), dispersed in oxygen-enriched perfluorocarbon (PFO), and crosslinked within a quaternary ammonium-modified hydrogel matrix possessing biofilm-penetrating capability. Upon US irradiation, the hydrogel achieves deep biofilm penetration and generates abundant reactive oxygen species (ROS) through Fe/Zn synergistic catalysis, while PFO liquefaction releases oxygen to alleviate local hypoxia and potentiate the sonodynamic effect. In a rat model of methicillin-resistant Staphylococcus aureus (MRSA)-induced tibial osteomyelitis, this treatment markedly reduced bacterial load, substantially suppressed inflammatory infiltration and pro-inflammatory cytokine cascades, and effective mitigation of bone erosion. Collectively, MIL-101(Fe)@ZnO@MM + PFO + Gel+US offers a minimally invasive, spatiotemporally controlled platform for eradicating refractory infections and reprogramming the osteomyelitic microenvironment toward regeneration.