ROS-Degradable Hyaluronic Acid–Vitamin D3 Nano-Micelles Reprogram Synovial Macrophages to Orchestrate Quad-Synergistic Therapy for Osteoarthritis

Osteoarthritis (OA) belongs to chronic progressive joint degeneration driven by an imbalance in synovial macrophage polarization, excessive oxidative stress, cartilage matrix degradation, and persistent pain. Current clinical treatments remain palliative and fail to reverse OA progression due to poor targeting, uncontrolled drug release, and off-target toxicity. Herein, we developed ROS-degradable hyaluronic acid-vitamin D3 nano-micelles loaded with emodin (HA@VD3-ED) for quad-synergistic therapy. The micelles feature a thioketal linker for ROS-responsive cleavage, a hyaluronic acid shell for CD44-targeting to synovial macrophages, a vitamin D3 core for stability and potential analgesia, and emodin for anti-inflammatory and antioxidant effects. In vitro, HA@VD3-ED was internalized via CD44-mediated endocytosis, reprogrammed M1 to M2 macrophages, reduced ROS, preserved mitochondrial function, and protected chondrocytes function. In MIA-induced OA rats, HA@VD3-ED specifically accumulated in inflamed joints, responsively released drugs, suppressed synovial inflammation, alleviated oxidative damage, reduced cartilage degeneration, and relieved mechanical hyperalgesia as well as gait disorders. Notably, this nanoplatform exerted anti-inflammatory, antioxidant, chondroprotective, and analgesic effects without systemic toxicity. Collectively, ROS-responsive HA@VD3-ED nano-micelles remodel the joint immune microenvironment and orchestrate quad-synergistic therapeutic effects, representing a promising, safe, and disease-modifying strategy for OA treatment.