Natural Polyphenol-Functionalized Schwann Cell-Derived Exosomes as a Temporal Neuromodulation Strategy for Diabetic Periodontitis Therapy

An interactive bidirectional relationship between periodontitis and diabetes poses great challenges for the treatment of diabetic periodontitis in clinical practice. The hyperglycemic inflammatory periodontal microenvironment is characterized by oxidative damage, chronic invasive infection, excessive inflammation, unbalanced immunomodulation, progressive neuropathy, diabetic vasculopathy, and uncoupled bone resorption and formation responses. The neuromodulation strategy holds great potential to mediate and coordinate temporally the complex microenvironment for diabetic periodontal regeneration. Herein, natural grape seed polyphenols (GSPs) were used to modify the surface of exosomes derived from Schwann cells (SC Exo) through polyphenolic polymerization and noncovalent interactions. The GSP-coated SC Exo (GSP@SC Exo) system demonstrated antibacterial and antioxidative properties. Furthermore, these GSP@SC Exo nanoparticles could induce axonal growth of dorsal root ganglia explants, production of anti-inflammatory factors, M2 polarization of macrophages, tube formation of human umbilical vein endothelial cells, and human periodontal ligament stem cell osteogenic differentiation in vitro. Additionally, diabetic periodontal destruction was reversed through nerve regeneration, anti-inflammatory effect, immunomodulation, neovascularization, and alveolar bone formation in vivo. Therefore, this study provided a facile and effective neural engineering strategy for guiding the treatment of diabetic periodontitis in clinical applications.