Injectable Ozone-Rich Nanocomposite Hydrogel Loaded with D-Mannose for Anti-Inflammatory and Cartilage Protection in Osteoarthritis Treatment

Osteoarthritis (OA) is a dynamic condition characterized by cartilage damage and synovial inflammation. Ozone (O₃) shows potential therapeutic effects owing to its anti-inflammatory properties; however, its high reactivity and short half-life substantially limit its effectiveness in OA treatment. In this study, an ozone-rich thermosensitive nanocomposite hydrogel loaded with D-mannose is developed for OA treatment. Briefly, O₃ is encapsulated in nanoparticles (NPs) composed of perfluorotributylamine and fluorinated hyaluronic acid to improve its stability. Next, D-mannose is conjugated with α-amino of the hydroxypropyl chitin (HPCH) via Schiff base to prepare MHPCH. These nanoparticles are encapsulated in MHPCH to produce O₃ NPs@MHPCH. In vitro cell experiments demonstrate that the O₃ NPs@MHPCH treatment significantly reduced VEGF and inflammation levels, accompanied by a decrease in inflammatory factors such as IL-1β, IL-6, TNF-α, and iNOS. Furthermore, O₃ NPs@MHPCH promotes the expression of collagen II and aggrecan and stimulates chondrocyte proliferation. Additionally, in vivo studies show that O₃ NPs@MHPCH significantly alleviated OA by reducing synovial inflammation, cartilage destruction, and subchondral bone remodeling. O₃ NPs@MHPCH offers a promising option for improving the efficacy of O₃ therapy and reducing the risk of synovial inflammation and cartilage degeneration in OA.