An Injectable Hydrogel Sustains Low-Dose Intra-Articular Glucocorticoid Exposure to Protect Cartilage in Osteoarthritis.

Intra-articular glucocorticoid (GC) injections provide rapid symptomatic relief in osteoarthritis (OA). However, repeated administration of conventional triamcinolone acetonide (TA) suspensions can generate recurrent high local drug exposure, which may contribute to cartilage degeneration. Although extended-release TA formulations have been developed to reduce burst exposure, achieving prolonged and stable intra-articular drug retention while preserving cartilage structure remains challenging. Here we report an injectable hyaluronic acid (HA) hydrogel that forms a stable intra-articular depot to sustain delivery of TA and control local GC exposure kinetics. Sustained low-dose GC exposure modulates macrophage-associated inflammatory responses, suppresses pro-inflammatory cytokine production, and preserves chondrocyte mitochondrial homeostasis under inflammatory stress. In both murine and load-bearing large animal goat OA models, TA-loaded HA hydrogel treatment improves functional performance, reduces synovial inflammation, and preserves cartilage structure and matrix integrity, as demonstrated by enhanced gait or mechanical pain thresholds and higher MRI-based MOCART 2.0 scores. Our findings indicate that tuning intra-articular GC pharmacokinetics can enhance therapeutic durability while promoting structural joint preservation in OA. STATEMENT OF SIGNIFICANCE: Intra-articular glucocorticoids are widely used in osteoarthritis, yet their clinical value is limited by rapid clearance, repeated dosing, and harmful peak exposure. This work introduces an injectable hyaluronic acid hydrogel that transforms glucocorticoid therapy from a short-lived anti-inflammatory injection into a controlled, cartilage-protective treatment. By establishing a stable intra-articular drug depot, the hydrogel reshapes local glucocorticoid exposure, suppresses destructive joint inflammation, promotes a reparative microenvironment, and preserves chondrocyte and matrix homeostasis. Importantly, these benefits were demonstrated not only in mice but also in a load-bearing goat model, highlighting a clinically relevant biomaterial strategy for safer and more durable structure-modifying osteoarthritis therapy.