sPLA2 inhibitor-loaded nanoparticles mitigate spontaneous osteoarthritis in guinea pigs

Osteoarthritis (OA) is a prevalent degenerative joint disease lacking effective disease-modifying therapies. Secreted phospholipase A2 (sPLA₂), a key upstream regulator of inflammatory lipid mediators, has been implicated in OA pathogenesis, but its therapeutic potential in age-related OA remains unclear. Here, we evaluated the role of sPLA₂ and the efficacy of nanoparticle-mediated sPLA₂ inhibition in a spontaneous OA model using female Dunkin-Hartley (DH) guinea pigs. We first characterized OA progression and observed age-dependent increases in cartilage degeneration, synovitis, oxidative stress, and sPLA₂ expression and enzymatic activity. We then developed sPLA₂ inhibitor (thioetheramide-PC)-loaded nanoparticles (sPLA₂i-NPs) and demonstrated their superior ability, compared to free inhibitor, to prevent IL-1β-induced cartilage degeneration in guinea pig cartilage explants. In vivo, intra-articular administration of sPLA₂i-NPs from 3 months of age significantly attenuated cartilage destruction, synovial inflammation, and osteophyte formation in 7- and 10-month-old guinea pigs. These structural improvements were accompanied by normalization of anabolic and catabolic gene expression and a marked reduction in synovial fluid sPLA₂ activity. Importantly, longitudinal gait analysis revealed that sPLA₂i-NP treatment preserved limb loading, propulsion, and locomotor performance, demonstrating functional recovery. No systemic toxicity was observed following long-term treatment. Collectively, our findings identify sPLA₂ as a key driver of spontaneous OA and establish nanoparticle-mediated sPLA₂ inhibition as a promising disease-modifying strategy for age-related OA.