MBene nanozyme orchestrates antibacterial and osteoimmune responses for synergistic therapy of methicillin-resistant Staphylococcus aureus-infected osteomyelitis

The deep-seated location of methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis within the host, combined with insufficient antibiotic penetration into bone and the capacity of MRSA to form biofilms, may render conventional therapies ineffective. A promising alternative is chemodynamic therapy (CDT), which locally generates cytotoxic hydroxyl radicals. However, the efficacy of such agents as monotherapy is significantly compromised by the hypoxic microenvironment characteristic of deep-seated bone infections. This study introduces a copper-doped molybdenum boride (Cu@MoB) nanozyme, which exhibits impressive photothermal conversion and multi-enzyme mimetic activities (oxidase and peroxidase), thereby enabling effective cooperative photothermal therapy (PTT) and CDT. In a mouse model of MRSA osteomyelitis, the PTT/CDT mediated by Cu@MoB successfully eradicated bacteria from the intramedullary space and enhanced the repair of the infected bone. Furthermore, it exhibited superior efficacy in vivo compared to vancomycin, the gold standard antibiotic currently employed in clinical practice. An increase in TGF-β levels in the bone marrow associated with inflammation was observed following treatment, indicating that the inhibition of the inflammatory microenvironment contributed to the effectiveness of treatment. Further transcriptomic sequencing analyses revealed that Cu@MoB downregulated the expression of pro-inflammatory genes, including Il1b, Il6, Tnf, and Ccl2, while inhibiting several inflammatory pathways, such as the Toll-like receptor, NF-κB, and Th17 pathways. Cu@MoB has the potential to serve as a MBene-based nanoplatform for the synergistic treatment of drug-resistant, deep-seated infections, representing a strategy for anti-infective bone defect repair. STATEMENT OF SIGNIFICANCE: The treatment of MRSA-induced osteomyelitis remains challenging due to the presence of deep-seated infection foci, biofilm formation, and limited antibiotic penetration. We developed a copper-doped MBene nanozyme (Cu@MoB) that integrates photothermal therapy and chemodynamic therapy into a single platform for synergistic antibacterial treatment. Unlike conventional approaches, our rationally designed Cu@MoB leverages copper doping to simultaneously enhance Fenton-like catalytic activity under near-physiological pH while maintaining excellent photothermal conversion efficiency. This work demonstrates, for the first time, that Cu@MoB-mediated PTT/CDT synergy not only eradicates intramedullary MRSA more effectively than vancomycin but also modulates the osteoimmune microenvironment by downregulating pro-inflammatory pathways (TLR, NF-κB, Th17) to promote bone regeneration. This approach offers a paradigm-shifting strategy for treating drug-resistant deep-seated infections.