DPSC-EVs Drive Functional Recovery in Sjögren's Disease by Systemic Immunomodulation.

Sjögren's disease (SjD) is a debilitating autoimmune disorder characterized by progressive salivary gland destruction, for which current therapies are merely palliative. Novel therapeutic approaches focusing on immunomodulation are therefore urgently needed. Extracellular vesicles from dental pulp stem cells (DPSC-EVs) have emerged as a promising cell-free platform for systemic immunomodulation. Here, we investigated the therapeutic efficacy of DPSC-EVs in a nonobese diabetic mouse model of SjD to elucidate the mechanistic basis for their superior immunomodulatory potential compared with bone-marrow-derived EVs (BMMSC-EVs). A single intravenous administration of DPSC-EVs significantly recovered salivary gland function, accompanied by a marked reduction in serum autoantibodies and glandular inflammation. DPSC-EVs preferentially accumulate in the spleen and are internalized by F4/80+ macrophages. This interaction triggered a dual modulation of transforming growth factor (TGF)-β/Smad signaling: (i) direct delivery of a higher TGF-β1 payload, initiating signaling and (ii) concurrent downregulation of the NEDD4L E3 ubiquitin ligase, which amplified and sustained the signal by inhibiting phosphorylated Smad2/3 degradation. Thus, DPSC-EVs exert their therapeutic effects by systemically targeting splenic macrophages to orchestrate a powerful, dual-mode activation of an immunoregulatory pathway. This study established DPSC-EVs as a highly promising, cell-free immunomodulatory therapy for SjD, offering a clear pathway for clinical translation.