An Apigenin-Based Bone-Targeted System Enhances Antioxidant Capacity of Bone Marrow Mesenchymal Stem Cells via the PI3K/Akt Pathway to Alleviate Osteoporosis

The primary etiology of osteoporosis (OP) is the imbalance of bone homeostasis, which is characterized by insufficient formation and excessive resorption. Current clinical drugs for osteoporosis often cause off-target toxicity due to their systemic effects. The osteoporotic bone microenvironment exacerbates oxidative stress in bone marrow mesenchymal stem cells (BMSCs), which in turn diminishes their osteogenic differentiation. Apigenin (API), a natural flavonoid compound, exhibits multitarget regulatory and antioxidant properties. However, its clinical application is limited by drawbacks such as low bone tissue bioavailability and rapid in vivo metabolism. Therefore, devising highly efficient bone-targeted delivery strategies is essential to surmounting its pharmacokinetic shortcomings. In vitro experiments demonstrated that API significantly enhanced the osteogenic differentiation of BMSCs sourced from osteoporotic donors (OP-BMSCs), reduced OP-BMSCs' reactive oxygen species (ROS) levels, and increased their mitochondrial membrane potential. Mechanistically, the integration of the inherent properties of API with RNA sequencing data suggests that the platform restores redox homeostasis in OP-BMSCs via the PI3K/Akt signaling axis, thereby promoting osteogenic differentiation. To address the bottleneck of the API's poor aqueous solubility and low utilization, we developed a BMSC-affinitive E7 peptide highly loaded with API (API@Lipo-E7). This system leverages the E7 peptide's specific recognition of BMSCs, significantly enhancing API enrichment in bone tissue. An in vivo fluorescence imaging study indicated the system's excellent bone-targeting capability. Therefore, Api-Lipo@E7 intervention by tail vein injection increased bone mineral density in ovariectomized (OVX) mice more efficiently than API alone, indicating that the bone-targeted delivery of API is essential for mitigating bone loss in OVX mice. This study elucidates the molecular mechanism by which the natural compound apigenin regulates OP-BMSCs, and its pharmacokinetic limitations are addressed with a smart delivery system, collectively offering a new strategy for the precise treatment of osteoporosis.