Conclusion
By using MOSCs that are highly reactive to ROS as drug-loaded matrices for the first time, this study provides an avenue for the management of severe joint inflammation by designing synergistic supramolecular drug-delivery systems with subcellular targeting and ROS-scavenging capacity.
Methods
In this study, we utilized a zinc-based metal-organic supercontainer (MOSC) as a proton sponge and electron reservoir with outstanding proton binding capacity, extracellular ROS-scavenging ability, and biocompatibility to establish an efficient supramolecular nanocarrier for endo/lysosomal escape and mitochondrial targeting. 4-Octyl itaconate (4-OI), an itaconate derivative, served as the loaded guest for the construction of a synergistic therapeutic system for inflammatory macrophages and OCs.
Results
After the effective encapsulation of 4-OI, 4-OI@Zn-NH-pyr not only exhibited potent ROS-scavenging capacity, but also reduced ROS production by mediating mitochondrial respiration in inflammatory macrophages. Regarding its anti-inflammatory efficacy, 4-OI@Zn-NH-pyr ameliorated the inflammatory reaction by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thus increasing the production of antioxidants, apart from the inhibition of NF-κB pathways. Additionally, receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and function was remarkably suppressed by 4-OI@Zn-NH-pyr. Consistent with in vitro observations, 4-OI@Zn-NH-pyr efficiently inhibited synovial inflammation and subchondral bone destruction in an acute arthritis model.