Targeting the IKKα/NF-κB Axis with SGEC-Derived Exosomal miR-23b-3p Rebalances Treg/Th17 Immunity in Sjögren’s Syndrome

Background: Sjögren’s syndrome (SS) is a systemic autoimmune disorder characterized by chronic inflammation, oxidative stress, and progressive salivary gland dysfunction. Current therapies remain limited in efficacy. Aim: This study explored the regulatory effect of exosome (Exo)-transported miR-23b-3p on the IκB kinase alpha (IKKα)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis in SS. Methods: Key SS-related microRNAs (miRNAs) were identified by integrating weighted gene co-expression network analysis with machine-learning-based transcriptomic profiling. Target genes and functional pathways were analyzed by bioinformatics methods. The direct binding between miR-23b and IKKα (CHUK) was validated by a dual-luciferase reporter assay. An in vitro SS cell model was established to examine the effects of miR-23b-3p on the IKKα/NF-κB pathway, oxidative stress, inflammation, and apoptosis. miR-23b-3p was loaded into salivary gland epithelial cell-derived Exos (SGEC-Exos) via electroporation. In vitro coculture experiments assessed reactive oxygen species (ROS) levels, inflammatory cytokines, Treg/Th17 balance, and cell apoptosis. In vivo effects were evaluated in NOD/Ltj mice by measuring salivary flow rate, histopathology, and expression of salivary-function-related proteins AQP5 and GPER. Results: SGEC-Exos@miR-23b-3p significantly suppressed IKKα expression and NF-κB activation, reduced ROS production, and modulated immune responses by restoring the Treg/Th17 balance. It also inhibited apoptosis by decreasing Bax and caspase-3 expression and increasing Bcl-2 levels. These effects were partially reversed by reactivation of the IKKα/NF-κB pathway. In NOD/Ltj mice, SGEC-Exos@miR-23b-3p improved salivary flow, alleviated glandular pathology, and upregulated AQP5 and GPER expression. Conclusions: SGEC-Exos@miR-23b-3p offers a translational approach to address oxidative stress, immune imbalance, and glandular injury in SS, highlighting the potential of Exo-based miRNA therapy. Antioxid. Redox Signal. 00, 000–000.