CircAars‐Engineered ADSCs Facilitate Maxillofacial Bone Defects Repair Via Synergistic Capability of Osteogenic Differentiation, Macrophage Polarization and Angiogenesis

Adipose-derived stem cells (ADSCs) hold significant promise in bone tissue engineering due to their self-renewal capacity and easy accessibility. However, their limited osteogenic potential remains a critical challenge for clinical application in bone repair. Emerging evidence suggests that circular RNAs (circRNAs) play a key role in regulating stem cell fate and osteogenesis. Despite this, the specific mechanisms by which circRNAs influence ADSCs in the context of bone tissue engineering are largely unexplored. This study introduces a novel strategy utilizing circAars, a specific circRNA, to modify ADSCs, which are then incorporated into gelatin methacryloyl (GelMA) hydrogels for the repair of critical-sized maxillofacial bone defects. The findings reveal that circAars predominantly localizes in the cytoplasm of ADSCs, where it acts as a competitive sponge for miR-128-3p, enhancing the osteogenic differentiation and migration capabilities of ADSCs. Furthermore, circAars-engineered ADSCs facilitate macrophage polarization from the M1 to M2 phenotype and enhance endothelial cell (EC) angiogenic potential through a paracrine mechanism. Additionally, GelMA scaffolds loaded with circAars-engineered ADSCs accelerate the repair of critical-sized maxillofacial bone defects by synergistically promoting osteogenesis, macrophage M2 polarization, and angiogenesis. This approach offers a promising therapeutic strategy for the treatment of critical-sized maxillofacial defects.