Remodeling of the pro-inflammatory microenvironment in osteoarthritis via hydrogel-based photothermal therapy

Osteoarthritis (OA) is a widespread joint disease, yet there are limited effective treatment strategies that preserve articular cartilage and mitigate damage to other joint elements. The role of inflammation is crucial, driving cartilage degeneration and synovitis in OA. While photothermal therapy (PTT) has shown promise in cancer and antibacterial treatments, its application in OA remains underexplored. In this study, we developed an optimized injectable hydrogel for PTT in OA, formulated by combining a hyaluronic acid (HA)-thiourea (NCSN) solution with Cu 2+ (HSC hydrogel). Leveraging the dynamic and reversible chelation between NCSN and Cu 2+ , this hydrogel exhibits significant photothermal properties. Furthermore, the unchelated NCSN aids in neutralizing excessive reactive oxygen species. As a result, the HSC hydrogel offers easy injectability, inherent self-healing properties, and potent photothermal performance, negating the requirement for external photothermal agents. In vitro analyses confirmed the non-cytotoxic feature of HSC hydrogel to chondrocytes. When combined with near-infrared (NIR) treatment (HSC/NIR), the hydrogel effectively bolsters chondrocyte anabolism while diminishing catabolism and inflammation triggered by IL-1β. In vivo studies highlight remarkable therapeutic potential of HSC/NIR in OA, demonstrating reductions in cartilage degeneration, synovitis, osteophyte formation, and subchondral sclerosis. Transcriptomic study illuminates the mechanism by which HSC/NIR counteracts IL-1β-driven chondrocyte transcriptomic shifts, particularly inhibiting the JAK/STAT signaling pathway and promoting cell proliferation. Additionally, HSC/NIR moderates macrophage polarization, mitigating the inflammatory milieu and consequently promoting chondrocyte anabolism and curtailing catabolism and inflammation. This study emphasizes the effect and strength of hydrogel-based PPT on cartilage homeostasis, inflammatory responses, and potential immune modulation, offering a new frontier in OA treatment paradigms. Graphical Abstract The study developed an optimized injectable hydrogel for photothermal therapy in osteoarthritis, focusing on the modulation of the inflammatory environment.