Multimodal modulation of metal-based nanomaterials in osteoarthritis immunotherapy: current landscape and future paradigms

Osteoarthritis (OA) is a degenerative joint disease characterized by immune-metabolic dysregulation, oxidative stress, and chronic inflammation. Current therapies offer symptomatic relief but do not halt disease progression. Metal-based nanomaterials (MNMs) have recently emerged as innovative immunomodulatory agents for OA treatment. This review summarizes key immune-pathological mechanisms in OA, such as macrophage polarization imbalance, NLRP3 inflammasome activation, and ferroptosis, and examines how MNMs mitigate these processes via ROS scavenging, macrophage reprogramming, and targeted inhibition of inflammatory signaling. We also highlight advanced material design strategies such as surface functionalization and stimulus-responsive drug release for improved targeting and efficacy. Despite promising preclinical results, challenges related to long-term biosafety and clinical translation remain. Future efforts should focus on rational nanomaterial design, mechanistic studies using advanced omics technologies, and the development of more physiologically relevant disease models to facilitate clinical application.