Targeting soluble PD-1 with a Sponge-like Exosome System alleviates renal interstitial fibrosis via restoring PD-1/PD-L1-mediated immunosuppression

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Targeting soluble PD-1 with a Sponge-like Exosome System alleviates renal interstitial fibrosis via restoring PD-1/PD-L1-mediated immunosuppression

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Co-author 1

Yuting Zhang zhangyuting_51@163.com Xijing Hospital, The Fourth Military Medical University Department of Nephrology Xi'an China *

Co-author 2

Lijie He helijie@fmmu.edu.cn Xijing Hospital, The Fourth Military Department of Nephrology Xi'an China -

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Introduction

Renal interstitial fibrosis (RIF) is a common pathological feature in chronic kidney disease (CKD), driven by sustained immune activation and dysregulated tissue repair. Soluble PD-1 (sPD-1), a variant of the membrane-bound immune checkpoint, has been implicated in inflammatory and fibrotic processes, though its role in RIF remains poorly defined. Elevated sPD-1 levels are associated with T-cell hyperactivation and progressive fibrosis, suggesting its potential as a therapeutic target. This study aimed to investigate the contribution of sPD-1 to RIF progression and to develop a targeted therapeutic strategy using engineered exosomes (Exo-PD1) for neutralization of circulating sPD-1, thereby attenuating T-cell-mediated fibrotic signaling.

Methods

We constructed a novel exosome-based system (Exo-PD1) displaying surface avidin and encapsulating anti-biotinylated PD-1 antibodies to specifically adsorb sPD-1. The system was evaluated in both in vitro models and in vivo animal experiments relevant to RIF. Fibrosis markers including α-SMA and collagen I were assessed using immunohistochemistry and molecular assays.

Results

Soluble PD-1 levels were significantly elevated in CKD patients with RIF and correlated with hyperactivated T-cell infiltration. Treatment with Exo-PD1 effectively neutralized circulating sPD-1, reduced T-cell activation, and suppressed pro-fibrotic signaling pathways. Exo-PD1 administration significantly downregulated key fibrosis markers (α-SMA, collagen I) in vitro and in vivo. The system demonstrated high targeting efficiency, strong sPD-1 adsorption capacity, and a favorable safety profile.

Conclusion

Soluble PD-1 plays a pivotal role in promoting renal interstitial fibrosis via sustained immune activation. The Exo-PD1 system represents a promising targeted therapeutic strategy for mitigating fibrosis in CKD by neutralizing sPD-1, with high translational potential for clinical application.

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