A Janus‐ROS Healing System Promoting Infectious Bone Regeneration via Sono‐Epigenetic Modulation

Abstract Elimination of bacterial infections and simultaneously promoting osteogenic differentiation are highly required for infectious bone diseases. Massive reactive oxygen species (ROS) can damage cells, while low ROS concentrations as a molecular signal can regulate cellular fate. In this study, a Janus‐ROS healing system is developed for infectious bone regeneration. An alendronate (ALN)‐mediated defective metal–organic framework (MOF) sonosensitizer is prepared, which can effectively clear Methicillin‐resistant Staphylococcus aureus (MRSA) infections and promote osteogenic differentiation under differential ultrasonic irradiation. In the presence of zirconium–phosphate coordination, the ALN‐mediated porphyrin‐based MOF (HN25) with a proper defect has great sonodynamic antibacterial efficiency (98.97%, 15 min) and bone‐targeting ability. Notably, under low‐power ultrasound irradiation, HN25 can increase the chromatin accessibility of ossification‐related genes and FOXO1 to promote bone repair through low ROS concentrations. Animal models of paravertebral infection, fracture with infection, and osteomyelitis demonstrate that HN25 successfully realizes the targeted and potent repair of various infectious bone tissues through rapid MRSA elimination, inhibiting osteoclast activity and promoting bone regeneration. The results show that high catalytic efficiency and bioactive MOF can be constructed using pharmaceutical‐mediated defect engineering. The Janus‐ROS treatment is also a promising therapeutic mode for infectious tissue regeneration.