Synergistic Osteogenic and Antiapoptotic Framework Nucleic Acid Complexes Prevent Diabetic Osteoporosis

Abstract Diabetes mellitus (DM) is characterized by elevated blood glucose and advanced glycation end product (AGEs) levels. Increased AGEs in bone tissue inhibit osteogenic differentiation by bone marrow mesenchymal stem cells (BMSCs), leading to bone loss and osteoporosis in diabetic patients. Enhancing the osteogenic differentiation capacity of BMSCs in the presence of abundant AGEs can improve bone health and prevent osteoporosis in DM patients. The flavonoid, Quercetin, has anti‐inflammatory, antibacterial, and antitumor properties; however, it is insoluble in water and thus not easily absorbed by the body. Nanodrug delivery systems such as tetrahedral framework nucleic acids (tFNAs) exhibit excellent biocompatibility, efficient cell uptake, and drug piggybacking. In the present study, tFNAs with quercetin is complexed to form a novel nanodrug (tFNAs/Que) that combined the features of both components. tFNAs/Que promote osteogenic differentiation by BMSCs in an in vitro AGEs‐rich environment, maintain bone mass, and prevent diabetic osteoporosis in DM mice in vivo. The mechanism of tFNAs/Que against AGEs may be related to the JNK signaling pathway. In conclusion, it is shown that tFNAs/Que has a dual regulatory role by promoting osteogenic differentiation and inhibiting apoptosis. Such a feature is promising for the prevention and treatment of diabetic osteoporosis.