Icaritin-Incorporated Porous Hollow Iron Oxide Nanostructures for Promoting Fracture Repair

Bone fracture is a huge medical and sociological problem. Among various therapeutic drugs, icaritin (ICA), as a novel natural osteoinductive agent, has attracted considerable attention due to its remarkable osteogenic effect, but it still has some drawbacks such as poor bone targeting and a rapid plasma clearance rate. Recently, iron oxide nanoparticles (IONPs) show increasingly potential as drug delivery vehicles to overcome these limitations. In this study, porous hollow iron oxide nanoparticles (PHNPs) were synthesized via thermal decomposition and controllable oxidation methods and ICA was incorporated during the hydrophilic phase transfer process. The preosteoblastic MC3T3-E1 cell line was used to evaluate their osteogenic effect, and the results demonstrated that ICA-incorporated PHNPs displayed superior biocompatibility and pronounced alkaline phosphatase activity and expression of osteogenic-related genes and proteins in a synergistic manner. Mechanistic investigations demonstrated that the MEK/ERK/p90RSK signaling pathway might provide a potential explanation for ICA-incorporated PHNP-mediated osteogenic differentiation. Furthermore, hyaluronic acid–cholesterol (HA–CHOL) was used to establish nanoclusters (ICA-PHNP-NCs) for in vivo bone regeneration assessment using a murine femur fracture as a model. The results showed that ICA-PHNP-NCs efficiently accumulated at the fracture site in the presence of a static magnetic field and accelerated fracture repair rapidly and effectively. For the first time, the dual application of osteogenic agents transport and ICA delivery using the ICA-PHNP-NC formulation was achieved against bone fracture, providing a new treatment strategy for diseases related to fractures.