Targeted Delivery of α‐ketoglutarate to Macrophages in Bone: A Novel Therapeutic Strategy for Improving Fracture Healing in Type 2 Diabetes

Impaired fracture healing is a common complication in type 2 diabetes mellitus (T2DM), with limited effective treatments. This study investigates the role of macrophages in bone repair and introduces a novel therapeutic strategy. Reduced glutaminase (GLS) expression and glutaminolysis are found in macrophages from T2DM mice and monocytes from T2DM patients. Specific deletion of GLS in macrophages altered their phenotypes and delayed fracture healing in mice. Mechanistically, GLS deficiency reduced α-ketoglutarate (α-KG) levels in macrophages, which impairs bone morphogenetic protein 2 (BMP2) production by increasing cytosine methylation on the promoter, ultimately hindering osteogenic differentiation of bone marrow mesenchymal stem cells. Importantly, while systemic α-KG supplementation deteriorates fracture healing in T2DM mice, a targeted delivery of α-KG using α-KG@Cy5.5@ALN-Liposome to macrophages in bone markedly improves fracture healing. These findings underscore the critical role of macrophage glutaminolysis in fracture healing and propose targeted α-KG delivery as a promising therapeutic intervention for improving fracture repair in T2DM patients.