Metformin-engineered Exosome-Based Scaffolds Promote Diabetic Bone Regeneration Via Soil-Seed Coordination of Inflammation and Mitochondrial Function

The regeneration of diabetic bone defects represents a significant clinical challenge due to impaired osteogenesis, angiogenesis, and a chronic inflammation. To address this gap, our study introduced a novel “seed-and-soil” coordinative intervention paradigm. Leveraging metformin’s anti-inflammatory and mitochondria-restoring actions, we engineered BMSCs-derived exosomes (Met-Exo) via metformin pretreatment, which were enriched with miRNAs targeting mitochondrial function, osteogenesis, and inflammation. Specifically, Met-Exo reprogrammed mitochondrial dysfunction of BMSCs under high glucose by restoring mitochondrial dynamics, scavenging reactive oxygen species (ROS), and improving energy metabolism, thereby enhancing osteogenic differentiation. Concurrently, Met-Exo induced macrophage polarization towards an anti-inflammatory M2 phenotype. This approach disrupted the vicious cycle of inflammatory microenvironment (“soil”) and mitochondrial dysfunction in BMSCs (“seeds”), offering a coordinated strategy that targets both the inflammatory milieu and dysfunctional cells. Met-Exo was then incorporated with a copper metal-organic framework into polycaprolactone (PCL) electrospun scaffolds, which provided sustained release of both Met-Exo and pro-angiogenic Cu²⁺ ions. In a rat model of diabetic bone defect, the scaffold significantly improved the inflammatory microenvironment and enhanced vascularized bone regeneration. This study demonstrates that the multifunctional scaffold, combining immunomodulatory and mitochondrially-reprogramming exosomes with a pro-angiogenic component, effectively overcomes the multifaceted barriers in diabetic fractures healing via “immune microenvironment-mitochondrial function-bone formation” temporal therapy, offering a “soil-seed” coordinated intervention for regenerative medicine.