Varespladib-Based Lipid Nanoparticles as Highly Efficient Anti-Inflammatory Agents for Osteoarthritis Treatment.

Osteoarthritis (OA) is often associated with chronic, unresolved inflammation in joint tissues, leading to cartilage degeneration. Secretory phospholipase A(2) (sPLA(2)) plays a crucial role in the pathogenesis of inflammatory diseases, and we previously found its amount in articular cartilage to be much higher in OA samples than healthy ones. In this study, we developed lipid nanoparticles carrying a potent, clinically investigated sPLA(2) inhibitor varespladib (Vare-LNPs) and evaluated their therapeutic efficacy in OA treatment. In vitro assays demonstrated that Vare-LNPs are stable and have high sPLA(2) inhibitory activity in solution and that they are nontoxic on primary chondrocytes. They penetrated deeply into the articular cartilage explants and exhibited prolonged retention in mouse OA joints as shown by in vivo imaging. Moreover, they completely mitigated OA development in articular cartilage explants following IL-1β treatment. In vivo, they effectively attenuated cartilage degeneration, synovitis, and joint pain in two mouse models of OA (destabilization of the medial meniscus and loading) by suppressing macrophage infiltration and joint inflammation. Von Frey assay further revealed their ability to ameliorate OA-related pain. Notably, these therapeutic effects were achieved at a low dosage and few injection frequencies. In summary, we developed a nanodrug that offers a potent and clinically translatable strategy for OA therapy by targeting joint inflammation.