Oleanolic Acid Liposomes Mitigate Knee Osteoarthritis by Remodeling Inflammatory Signaling and Cartilage Matrix Homeostasis

Abstract Knee osteoarthritis (KOA) is a chronic degenerative joint disease driven by persistent inflammation, synovial activation, and progressive cartilage matrix degradation, yet effective local therapeutic strategies remain limited. Oleanolic acid (OLA), a natural pentacyclic triterpenoid with anti-inflammatory and chondroprotective activities, is constrained by poor aqueous solubility and limited bioavailability. Here, we engineered OLA-loaded liposomes as a nanoscale delivery platform to improve the local applicability of OLA for KOA therapy. The liposomes were fabricated by thin-film hydration and systematically characterized by high-performance liquid chromatography (HPLC), dynamic light scattering (DLS), transmission electron microscopy (TEM), and stability analysis. Their therapeutic performance was evaluated in a papain-induced rat KOA model and in lipopolysaccharide (LPS)-stimulated fibroblast-like synoviocytes (FLS) and RAW264.7 macrophages. Integrated network pharmacology and molecular docking identified the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling axis as a potential regulatory pathway. In vivo and in vitro analyses demonstrated that OLA-loaded liposomes markedly reduced knee swelling, inhibited inflammatory cytokine production, attenuated synovial inflammation, and preserved cartilage integrity by restoring collagen II (COL II) expression and suppressing matrix metalloproteinase 13 (MMP13). These findings establish OLA-loaded liposomes as a promising nanoenabled therapeutic strategy for local KOA treatment and provide mechanistic insight into their anti-inflammatory and chondroprotective actions.