A dual-functional Janus nanofibrous membrane as an immunomodulatory barrier for periodontitis regeneration under diabetic conditions

Periodontitis and diabetes mellitus exhibit a well-established bidirectional relationship, creating a hostile microenvironment characterized by persistent inflammation, oxidative stress, and impaired osteogenesis. Conventional guided tissue regeneration (GTR) membranes often yield suboptimal regenerative outcomes under these diabetic conditions due to their passive, monolithic structure. To address this limitation, we developed a novel dual-functional bilayer nanofibrous membrane, termed Pn@Janus TPP, through rational structural design specifically tailored for diabetic periodontitis. This Janus membrane features an anisotropic architecture: a dense barrier layer effectively blocks the infiltration of fast-proliferating soft tissue cells, while an opposite porous layer is functionalized with a polyethylene glycol (PEG) hydrogel incorporated with nano-hydroxyapatite (nHA) to enhance hydrophilicity, sustained Ca 2+ release, and osteoconductivity. Critically, the integration of tea polyphenol-functionalized graphene oxide (TPG) provides potent reactive oxygen species (ROS)-scavenging capacity, effectively mitigating the exacerbated oxidative stress characteristic of the diabetic periodontitis milieu. Under AGE (100 μg/mL) and LPS (100 ng/mL) conditions in vitro, the membrane significantly promoted the adhesion and osteogenic/cementogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), while concurrently exhibiting potent ROS-scavenging capacity. In vivo, Pn@Janus TPP implantation markedly enhanced alveolar bone regeneration in a diabetic rat periodontitis model, restored periodontal architecture, and reduced the expression of key pro-inflammatory cytokines (IL-6, TNF-α, iNOS, IL-1β), without inducing systemic toxicity. Transcriptomic and molecular analyses revealed that the therapeutic effects were mediated, at least in part, through the suppression of the IL-17/TRAF-6/NF-κB signaling axis. The innovative Janus structure, combining spatially resolved physical barrier function with bioactive immunomodulation and osteogenesis promotion, positions Pn@Janus TPP as a promising advanced biomaterial for managing the complex regenerative demands of diabetic periodontitis. • A dual-functional Janus nanofibrous membrane (Pn@Janus TPP) is engineered for diabetic periodontitis regeneration. • The membrane combines a dense barrier layer with a porous PEG/nHA hydrogel-functionalized layer for anisotropic biofunctionality. • TPG integration confers potent ROS-scavenging ability, mitigating oxidative stress in diabetic inflammatory microenvironments. • The membrane promotes osteogenic/cementogenic differentiation of BMSCs under high-glucose and inflammatory conditions. • In vivo, Pn@Janus TPP enhances alveolar bone regeneration and suppresses the IL-17/TRAF-6/NF-κB signaling axis. • The system demonstrates excellent biocompatibility, mechanical stability, and clinical potential for guided tissue regeneration.