Zhiyao Li, Shanshan Yuan, Chenchen Gong, Qiao Li, Chongzhi Wu, Qianqian Liu, Guiyang Zhang, Yuejie Ai, Wei Yang, Ronglin Chen, Bowen Li
Osteoarthritis (OA), a prevalent degenerative joint disorder, is marked by chronic inflammation, oxidative stress, and cartilage degradation within a complex pathological microenvironment. Current monotherapies offer limited efficacy and fail to address the multifactorial nature of OA. To overcome these limitations, we developed a multifunctional self-assembling nanoprodrug W/KGN@DSeD nanoparticles (NPs) for precise and synergistic OA therapy. The system integrates a microenvironment-responsive diselenide-bridged prodrug (DSeD) of diclofenac (DIC) and the chondrogenic agent kartogenin (KGN), codelivered via nanoparticles modified with a cartilage-targeting peptide (WYRGRL). In the OA microenvironment, elevated ROS cleaves the diselenide bonds within DSeD, releasing DIC, KGN, and selenium (Se). The released Se activates the Nrf2 pathway, promoting antioxidant defense and protecting chondrocytes from oxidative stress. Concurrently, KGN promotes the production of ECM, facilitating cartilage regeneration and contributing to microenvironmental remodeling, while DIC mitigates inflammation and alleviates pain. In OA mouse models, W/KGN@DSeD NPs exhibit targeted cartilage accumulation, sustained retention, enhanced microenvironment modulation, and robust therapeutic efficacy. This ingenious diselenide-bond-based self-assembling nanoprodrug offers a promising strategy for microenvironment-adaptive, multimodal OA treatment.