Ginsenoside CK Hybrid Exosome Composited Injectable Macroporous Hydrogel Scaffold for Cartilage Regeneration via Endogenous Bone Marrow Mesenchymal Stem Cells Recruitment and Fate Modulation

Osteoarthritis (OA)‐induced cartilage repair critically relies on bone marrow mesenchymal stem cells (BMSCs). Three key challenges persist in OA therapy: efficient recruitment of BMSCs to lesions, sustained retention in defects, and inhibition of chondrocyte hypertrophy under inflammatory conditions. This study proposes a multidimensional repair strategy coordinating the entire process of “endogenous BMSCs recruitment—retention/proliferation—differentiation—postdifferentiation fate‐regulation.” Accordingly, a ginsenoside CK (CK)‐hybridized exosome (HyExo@CK) composite injectable microporous hydrogel scaffold (HyExo@CK/SiCH) is developed by integrating material strategies for multifunctional synergy. Detailly, the HyExo@CK enables endogenous BMSCs recruitment. The hydrogel scaffold, formed by in situ polysiloxane crosslinking of silane‐modified recombinant collagen (functioning as surfactant‐like foaming agent) and hyaluronic acid (serving as a high‐viscosity rheological modifier and foam stabilizer), features interconnected macropores (171.40 ± 7.37 µm) that offer an optimal niche for BMSCs retention and proliferation. Cellular assays demonstrated HyExo@CK/SiCH significantly promoted BMSCs proliferation, migration, and chondrogenic differentiation. Computational modeling and OA‐mimicking transcriptomic analysis revealed that CK competitively binds to the ligand‐binding domain of SDF‐1, effectively inhibiting the chondrocyte hypertrophy‐associated SDF‐1/CXCR4 signaling pathway to regulate BMSCs fate postdifferentiation. In rabbit OA cartilage defect models, HyExo@CK/SiCH achieved complete cartilage regeneration within 12 weeks postimplantation, demonstrating superior endogenous BMSCs recruitment and whole‐cycle fate regulation capabilities.