Bioengineered anti-EpCAM-guided exosome nanocarriers delivering Foxp3 agonist butyrate achieve tissue-specific immunomodulation in autoimmune Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is characterized by salivary gland-centered immune dysregulation, in which an imbalanced T follicular helper (Tfh)/T follicular regulatory (Tfr) axis drives aberrant follicular responses and glandular dysfunction. In this study, we developed an engineered exosome-based therapeutic platform (Exo@But-αEpCAM) by combining CD4+ T cell-derived exosomes, anti-EpCAM antibody-mediated targeting, and sodium butyrate as a Foxp3 agonist. The engineered exosomes exhibited stable antibody modification and efficient drug loading while preserving vesicle integrity and biosafety. Under inflammation-mimicking conditions relevant to pSS, Exo@But-αEpCAM displayed microenvironment-sensitive drug release. In vitro studies using peripheral blood mononuclear cells (PBMCs) from patients with pSS demonstrated that Exo@But-αEpCAM effectively restored the Tfh/Tfr balance by enhancing Foxp3-associated regulatory pathways and suppressing Tfh-related signaling, leading to reduced B cell activation. In a murine model of pSS, targeted exosome treatment preferentially accumulated in salivary glands, significantly improved salivary secretion, alleviated histopathological inflammation, and re-established local immune homeostasis without inducing systemic toxicity. Mechanistically, transcriptomic and proteomic analyses revealed that Exo@But-αEpCAM attenuated Tfh-driven follicular responses through inhibition of the IL-21R/STAT3 signaling axis. Collectively, this work presents a targeted and immunoregulatory exosome-based strategy that reconstructs immune homeostasis rather than broadly suppressing immunity, providing a promising therapeutic approach for pSS.