A DNA Tetrahedron Delivery Asiatic Acid to Reprogram Mitochondrial Metabolism for Promoting Bone Regeneration via STAT3 Phosphorylation

Abstract Craniofacial bone defects remain a significant clinical challenge due to the complex healing process among immune regulation, vascularization, and osteogenesis. Asiatic acid (AA), a natural pentacyclic triterpenoid, has shown promise in modulating inflammation and promoting bone repair, yet its clinical application is hampered by poor solubility, low bioavailability, and lack of targeted delivery. Here, a multifunctional hydrogel‐integrated DNA nanostructure system is reported, in which AA‐loaded DNA tetrahedra are embedded within a Hyaluronic Acid Methacrylate (HAMA) hydrogel（HM‐TDN@AA） to enhance local retention, bioavailability, and controlled release. The HM‐TDN@AA system significantly inhibited osteoclastogenesis and enhanced the osteogenic and angiogenic activity of mesenchymal stem cells and endothelial cells, respectively. In vivo implantation in a calvarial defect model revealed early enhancement of vascularization and remodeling of the immune niche, followed by robust bone formation. Transcriptomic profiling of bone tissue uncovered a metabolic reprogramming signature characterized by activation of mitochondrial oxidative phosphorylation (OXPHOS) pathways. Network pharmacology and molecular docking further identified STAT3 as a key regulatory node targeted by AA. Collectively, the findings demonstrate that the HM‐TDN@AA platform orchestrates bone regeneration by simultaneously modulating inflammation, angiogenesis, and cellular metabolism. This study provides a novel strategy that integrates nanostructure‐assisted drug delivery with metabolic control to enhance osteoimmune coupling and vascularized bone regeneration.