From overcoming to exploiting hypoxia: a metronidazole-armed type I photosensitizer for septic arthritis therapy

Septic arthritis is a life-threatening joint infection with high mortality, yet clinical antibiotic and surgical treatments usually cause increasing drug resistance and irreversible tissue damage. Photodynamic therapy (PDT) offers a non-invasive alternative with low drug resistance. However, its efficacy in septic arthritis is severely hampered by the intra-articular hypoxia. To address this issue, we propose an innovative strategy that shifts from overcoming hypoxia to fully exploit hypoxia. Accordingly, we developed a metronidazole-functionalized Type I cationic photosensitizer (PS), ACR-DM-MNZ. It anchors onto bacterial surfaces via electrostatic interactions and, importantly, leverages hypoxia-overexpressed nitroreductase to reduce its nitro group, thereby enhancing bacterial membrane binding and toxicity. Upon white light irradiation, it generates hydroxyl radicals (˙OH) to kill bacteria and eliminate biofilms. In a murine model of MRSA-induced septic arthritis, under light irradiation, ACR-DM-MNZ effectively eradicated intra-articular pathogens, alleviated joint swelling, modulated inflammation, reduced histopathological damage, and promoted joint repair. This work presents an efficient strategy that transforms the hypoxic barrier into a therapeutic asset, offering a promising platform for the treatment of septic arthritis.