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

Abstract Osteoarthritis (OA) is a dynamic condition characterized by cartilage damage and synovial inflammation. Ozone (O 3 ) 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, O 3 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 O 3 NPs@MHPCH. In vitro cell experiments demonstrate that the O 3 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, O 3 NPs@MHPCH promotes the expression of collagen II and aggrecan and stimulates chondrocyte proliferation. Additionally, in vivo studies show that O 3 NPs@MHPCH significantly alleviated OA by reducing synovial inflammation, cartilage destruction, and subchondral bone remodeling. O 3 NPs@MHPCH offers a promising option for improving the efficacy of O 3 therapy and reducing the risk of synovial inflammation and cartilage degeneration in OA.