ROS-mediated liposomal dexamethasone: a new FA-targeted nanoformulation to combat rheumatoid arthritis via inhibiting iRhom2/TNF-α/BAFF pathways

Rheumatoid arthritis (RA) is a worldwide autoimmune inflammatory disorder that seriously affected human health and its current management requires more successful therapeutic approaches. The combination of nanomedicines and pathophysiology into one system may provide an alternative strategy for precise RA treatment. In this work, a practical ROS-mediated liposome, abbreviated as Dex@FA-ROS-Lips that comprised of synthetic dimeric-thioether lipids (di-S-PC) and surface functionalized with folic acid (FA) was highlightly proposed for dexamethasone (Dex) delivery. Incorporating with thioether lipids and FA segment significantly improved the triggered release and RA active target of cytotoxic Dex, altering its overall pharmacokinetics and safety profiles in vivo. As proof, the designed Dex@FA-ROS-Lips demonstrated effective internalization by LPS-activated Raw264.7 macrophages with FA receptor overexpression and released Dex at the inflammatory site due to the ROS-triggered disassembles. Intravenous injection of these Dex@FA-ROS-Lips to adjuvant-induced arthritis (AIA) mice led to the incremental accumulation in inflamed joint tissues and significantly alleviated the cartilage destruction and joint swelling via suppression of proinflammatory cytokines (iRhom2, TNF-α and BAFF), as compared to the effect of commercial free Dex. Importantly, Dex@FA-ROS-Lips nanoformulation showed better hemocompatibility with less adverse effects on the body weight and immune organ index of AIA mice. The anti-inflammatory mechanism of Dex@FA-ROS-Lips was further studied and found it possibly associated with down-regulation of iRhom2 and activation of TNF-α/BAFF signaling pathway. Therefore, the integration of nanomedicines and RA microenvironment using multifunctional Dex@FA-ROS-Lips shall be a novel RA treatment modality with full clinical potential, and based on the enhanced therapeutic effect, the signaling pathway of iRhom2/TNF-α/BAFF was reasonably explained the mechanism of Dex@FA-ROS-Lips in anti-RA, which suggested a molecular target for RA therapy and other inflammatory diseases.