Self‐Assembling Hybrid Hydrogel Reprograms the Stromal Vascular Fraction to Treat Osteoarthritis

ABSTRACT Osteoarthritis (OA) is characterized by progressive cartilage degradation accompanied by limited intrinsic repair capacity. Stromal vascular fraction (SVF) transplantation has demonstrated potential for regenerating damaged joint tissue; however, the pathological microenvironment impairs SVF stemness, thereby limiting therapeutic efficacy. Herein, we developed a bioinspired hydrogel formed via the cross‐linking of hyaluronic acid‐grafted dopamine and a fibroblast growth factor 2‐mimetic peptide‐modified RADA16‐I. This injectable hydrogel combined excellent gelation performance with multifunctionality, particularly in enhancing SVF proliferation and chondrogenic differentiation. The hydrogel activated forkhead box M1 (FOXM1) – mediated epigenetic reprogramming, enhancing DNA repair capacity and increasing chromatin accessibility at pluripotency loci. In a rat OA model, combined hydrogel and SVF transplantation significantly enhanced articular cartilage regeneration and ameliorated OA symptoms. This study provides preliminary evidence showing that a biomaterial‐mediated epigenetic reprogramming strategy improves recovery in OA, highlighting the therapeutic potential of the novel hydrogel for stem cell‐based regenerative medicine.