Background: Treatment of cartilage lesions is clinically challenging. A previous study demonstrated that a hyaluronic acid hydrogel ( m-HA) with kartogenin (KGN)-loaded PLGA nanoparticles ( m-HA+KGN treatment) achieved superior cartilage repair in a rabbit model. However, large animals serve as a bridge to translate animal outcomes into the clinic. Hypotheses: (1) m-HA+KGN treatment could facilitate hyaline cartilage and subchondral bone tissue repair in a porcine model. (2) Defect size and type (full-thickness chondral vs osteochondral) influence the therapeutic efficacy of m-HA+KGN treatment. Study Design: Controlled laboratory study. Methods: 48 minipigs were randomized into 3 treatment groups: m-HA hydrogel with KGN-loaded PLGA nanoparticles ( m-HA+KGN treatment), m-HA hydrogel ( m-HA treatment), and untreated (blank treatment). Full-thickness chondral (6.5 mm or 8.5 mm in diameter) or osteochondral (6.5 mm or 8.5 mm in diameter; 5-mm depth) defects were prepared in the medial femoral condyle. At 6 and 12 months postoperatively, defect repair was assessed by macroscopic appearance, magnetic resonance imaging (MRI), micro–computed tomography (µCT), and histologic and biomechanical tests. Results: The m-HA+KGN group exhibited superior gross and histological healing after evaluation at 6 and 12 months postoperatively. Improved quality of the repaired cartilage demonstrated by MRI and better subchondral bone reconstruction assessed by µCT were observed in the m-HA+KGN group. The m-HA+KGN group showed more hyaline-like cartilage exhibited by histological staining in terms of extracellular matrix, cartilage lacuna, and type II collagen. The biomechanical properties were improved in the m-HA+KGN group. With m-HA+KGN treatment, defects with a diameter of 6.5 mm or full-thickness chondral-type defects possessed significantly higher ICRS macroscopic and histological scores compared with diameter 8.5 mm or osteochondral-type defects. Conclusion: (1) m-HA+KGN treatment facilitated hyaline cartilage and subchondral bone t...