Microwave-activated heterometallic MOF nanotransducer triggers disulfide stress-mediated metabolic collapse for refractory osteomyelitis treatment and bone regeneration

Refractory osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) remains a formidable clinical challenge due to persistent biofilm infection, antibiotic resistance, and impaired bone regeneration. Herein, we report a microwave-responsive heterometallic metal-organic framework (MOF) nanotransducer, MnZnHHTP, engineered through intrinsic electronic structure modulation for antibiotic-free osteomyelitis therapy. The microwave-responsive and catalytic properties were characterized by physicochemical, electromagnetic, electrochemical, spectroscopic, and theoretical analyses. The integrated Mn-O-Zn coordination network synergistically optimizes ionic conduction, charge delocalization, and microwave energy coupling, resulting in enhanced microwave-to-thermal conversion (ΔT ≈ 25.2 °C within 15 min) and catalytic reactive oxygen species (ROS) generation. Under microwave irradiation, MnZnHHTP achieves near 99.9% MRSA eradication through a previously underexplored antibacterial mechanism involving sulfur metabolic disruption, cysteine depletion, disulfide accumulation, and ultimately disulfide stress-mediated metabolic collapse. This self-amplifying redox crisis simultaneously restores MRSA susceptibility to multiple antibiotics, with combined treatment reducing CFU from 10 6 to below 40. Beyond antibacterial activity, MnZnHHTP promotes osteogenic differentiation by enhancing SOD2-mediated mitochondrial function, intracellular calcium deposition, and osteogenic gene expression. In an MRSA-infected osteomyelitis model, MnZnHHTP combined with microwave activation achieves 99.23% infection eradication, suppresses inflammatory responses, and accelerates bone regeneration, outperforming vancomycin therapy. This work establishes a mechanism-guided heterometallic MOF nanotransducer platform that integrates microwave catalytic therapy, bacterial metabolic collapse, and bone regeneration, providing a promising strategy for antibiotic-free treatment of deep-seated bone infections.