Immunomodulatory cytoskeleton of bionic periosteum affects mitochondrial dynamics to promote osteogenesis

Purpose: Periosteum is a key regulatory hub in the immune microenvironment of bone repair and the mitochondrial dynamics of bone marrow mesenchymal stem cells (BMSCs) directly determine the osteogenic efficiency; therefore, how to promote bone healing through the immunomodulation of mitochondrial dynamics is a key challenge. Methods: Inspired by the natural periosteum, we designed a bionic periosteum that integrates topology and controlled Semaphorin 3 A (Sema3A) release. Hyaluronic acid-coated Sema3A granular microsols spontaneously formed a nucleus-sheath structure under a high-voltage electric field to facilitate efficient drug loading. Results: The periosteum controlled Sema3A release and oriented topography, which drived macrophage M2 polarization via the PI3K/Akt/mTOR pathway, reconstructed the BMSC skeleton via the ROCK2 pathway, and synergistically promoted bone formation by driving mitochondrial fusion through material-appropriate stiffness. In vivo experiments further demonstrated that this biomimetic periosteum efficiently repaired bone defects by activating the immune microenvironment to remodel the BMSC skeleton and modulating mitochondrial dynamics, an endogenous repair cascade. Conclusion: This immunomodulatory drug delivery strategy utilizing bionic periosteum offers a novel approach for regenerative medicine to regulate immune-osteogenic crosstalk, which is promising for potential applications.