Cartilage-affinity tea polyphenol liposomes alleviate osteoarthritis by suppressing the PI3K/Akt signaling pathway

Tea polyphenols preserves chondrocyte homeostasis by mitigating mitochondrial stress. • Tea polyphenols protects chondrocytes by suppressing the PI3K/Akt signaling pathway. • Cartilage-affinity liposomes enhance local retention and in vivo efficacy of Tp. Tea polyphenols (Tp) have been reported to possess anti-inflammatory and antioxidant properties, but their application in osteoarthritis (OA) therapy is limited by poor bioavailability and lack of mechanistic clarity. Here, we show that Tp attenuates IL1β-induced chondrocyte inflammation, oxidative stress, and catabolic gene expression (MMP13, MMP3, ADAMTS5) while restoring COL2 levels. Transcriptomic analysis identifies the PI3K/Akt pathway as a key mediator of Tp’s chondroprotective effects, which was confirmed using the PI3K/Akt agonist YS-49. Tp also preserves mitochondrial membrane potential and reduces mitochondrial ROS production. To improve intra-articular delivery, we developed a cartilage-affinity peptide-modified liposomal nanocarrier (LipTp-T) with favorable size, stability, high encapsulation efficiency, and good biosafety. The peptide modification enhances chondrocyte uptake and prolongs joint retention beyond one week. In a mouse OA model, LipTp-T outperforms free Tp in preserving cartilage integrity, lowering OARSI scores, and suppressing ADAMTS5 and MMP13 expression, while consistently inhibiting the PI3K/Akt axis. Collectively, these findings demonstrate that Tp protects against OA by suppressing the PI3K/Akt pathway, and that cartilage-targeted liposomal delivery significantly enhances its therapeutic efficacy. Download: Download high-res image (193KB) Download: Download full-size image