Oxygen-supplying nanotherapeutics for bacterial septic arthritis via hypoxia-relief-enhanced antimicrobial and anti-inflammatory phototherapy.

Bacterial septic arthritis, an inflammatory disease caused by bacterial infections, is often accompanied by the emergence of multidrug-resistant bacteria, making therapeutic treatment a formidable challenge. With the emergence of antibiotic resistance, research on antimicrobial photodynamic therapy (aPDT) has regained attention. However, insufficient singlet oxygen production due to the hypoxia in the infection microenvironment is recognized as a key limiting the efficacy of aPDT. Hence, in this study, we designed a bacteria-targeted liposomal nanoplatform (MCPL) to alleviate hypoxia in the infectious microenvironment and enhance aPDT for bacterial septic arthritis. The nanoplatform was developed by integrating the phototherapeutic agent CyI and small-sized Pt NPs into thermosensitive liposomes, with modification of maltohexose on the liposome surface. In vitro and in vivo studies showed that MCPL could specifically target bacterial cell membranes and be thermally activated to catalytically convert endogenous hydrogen peroxide (H2O2) in the septic joint, supplementing local O2 reservoirs. This, in turn, supplies additional substrate pools for photodynamic conversion into reactive oxygen species (ROS) with bacterial toxicity. Furthermore, the antibacterial mechanism revealed that MCPL can regulate the HIF-1α and NF-κB signaling pathways in immune cells, acting as an effective modulator of antioxidant and anti-inflammatory pathways in both macrophages and neutrophils. This study demonstrates that MCPL could not induce bacterial multidrug resistance and provide as an innovative approach for treating bacterial septic arthritis.