Macrophage-Targeting Biomaterials for Osteoarthritis Therapy.

Osteoarthritis (OA) is a highly prevalent, disabling, and painful disease of the joints, characterized by progressive cartilage degeneration, synovial fibrosis, and pain. Mounting evidence highlights synovial inflammation as a key driver of OA pathogenesis, underscoring its contributive role at all disease stages. Among immune cells, macrophages, central components of the innate immune system, play a pivotal role by releasing inflammatory mediators, growth factors, and proteolytic enzymes that drive joint damage. Traditionally, drug delivery strategies sought to avoid macrophage uptake; however, recent advances have shifted toward exploiting macrophages as therapeutic targets to modulate inflammation and promote tissue repair. Targeting macrophages and abating their associated inflammatory pathways offers the potential to slow OA progression. Despite this promise, our understanding of synovial macrophage biology remains limited, and therapeutic interventions have achieved only modest success. Selectively targeting macrophage subsets or specific signaling pathways may reduce systemic side effects and enhance therapeutic precision. This review summarizes current knowledge on macrophage involvement in OA pathogenesis and highlights emerging biomaterials and nanotechnology-based strategies for macrophage targeting and reprogramming. Finally, it underscores the need for robust preclinical models and well-designed clinical trials to translate macrophage-targeted therapies into effective disease-modifying treatments for OA.