<p>Type 2 diabetes mellitus (T2DM) disrupts bone metabolism, exacerbating craniomaxillofacial bone loss and impairing the efficacy of regenerative therapies. While mesenchymal stromal cell (MSC)-based approaches, including MSC-derived cell aggregates (CAs), have shown promise in tissue regeneration across multiple organs, their regenerative capacity is significantly compromised in recipient diseased microenvironments. Here, using a high-fat diet (HFD)-induced T2DM murine model, this study reveals that CA implantation fails to boost osteogenesis or restore mandibular bone defects in diabetic mice due to systemic metabolic dysregulation. To address this limitation, we propose a combinatorial strategy integrating CAs with recipient periodic fasting, a metabolic intervention shown to alleviate lipidemia thus creating a beneficial condition for regeneration. Remarkably, the combined therapy enhances osteogenesis and safeguards mandibular bone regeneration in diabetic mice, evidenced by increased trabecular bone volume, reduced trabecular spacing, and elevated RUNX2 expression in defect areas. This combinatorial approach overcomes the limitations of standalone MSC therapies, highlighting the importance of addressing both local tissue repair and systemic metabolic dysregulation in diabetic bone regeneration. The findings propose a novel strategy integrating cellular engineering with metabolic interventions to optimize tissue regeneration in T2DM-related complications, offering translational potential for improving dental rehabilitation in diabetic patients.</p>