Soluble PD-1 drives renal fibrosis in CKD by disrupting immune homeostasis: Therapeutic mitigation via a targeted sPD-1 sequestration strategy

AIMS: Renal interstitial fibrosis (RIF) drives chronic kidney disease (CKD) progression, with elevated soluble PD-1 (sPD-1) exacerbating chronic inflammation. This study aims to elucidate the pathogenic role of sPD-1 in RIF and evaluate "Exo-PD1"-a novel engineered extracellular vesicle strategy designed to sequester circulating sPD-1-as a targeted therapeutic intervention to mitigate renal fibrosis. MATERIALS AND METHODS: We analyzed serum and renal biopsy samples from clinical CKD cohorts and three distinct mouse models-unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI), and aristolochic acid I (AAI)-induced nephropathy-using ELISA, immunohistochemistry, and flow cytometry. Exo-PD1 was engineered by surface-functionalizing extracellular vesicles with avidin to load anti-PD-1 antibodies. The therapeutic efficacy and safety profiles of Exo-PD1 were systematically evaluated in vitro and in vivo. KEY FINDINGS: Elevated sPD-1 strongly correlated with RIF severity and T-cell hyperactivation in both patients and murine models, while exogenous sPD-1 exacerbated fibrosis. Exo-PD1 effectively sequestered circulating sPD-1, outperforming conventional antibodies through local adsorption. Furthermore, Exo-PD1 treatment significantly attenuated T-cell hyperactivation, blunted inflammatory responses, and reduced key fibrotic markers (α-SMA, collagen I) across models with minimal systemic toxicity. SIGNIFICANCE: sPD-1 acts as a critical mediator of renal fibrosis by disrupting immune homeostasis. The biocompatible Exo-PD1 platform effectively intercepts circulating sPD-1, disrupting the inflammation-fibrosis crosstalk and offering a highly translational therapeutic approach to halt CKD progression.