Targeting Strategies for Osteoarthritis: Biomaterials, Joint-Specific Drug Delivery, and Translational Progress.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive destruction of joint structures and loss of mobility. The efficacy of current therapies is limited by the dense extracellular matrix of cartilage, rapid drug clearance by synovial fluid, and the complex anatomical and biomechanical features of specialized fibrocartilaginous and cartilaginous tissues such as the intervertebral disc, meniscus, and temporomandibular joint (TMJ) disc. Recent advances highlight the potential of exploiting OA-specific microenvironmental cues-most notably acidic pH and elevated reactive oxygen species (ROS)-to achieve targeted and responsive treatment. This review first introduces bioreactor technologies that simulate physiological and pathological joint environments, providing powerful platforms for studying OA pathogenesis and screening therapies. We then examine microscopic changes in joint structure, composition, and mechanical properties that represent both barriers and therapeutic opportunities. Particular emphasis is placed on smart biomaterials that respond to pH or ROS for site-specific drug delivery and controlled release. In addition, we summarize tissue-specific targeting strategies for superficial and deep cartilage layers and discuss delivery systems tailored to complex joint structures. Finally, we outline translational progress, including disease-modifying osteoarthritis drug candidates and clinically tested delivery systems, and highlight emerging approaches that may bridge laboratory research and clinical application.