Targeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis

Xudong Tang, Yangyang Shang, Hong Yang, Yalan Song, Shan Li, Yusi Qin, Jingyi Song, Kang Chen, Yang Liu, Dinglin Zhang () and Lei Chen ()
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Xudong Tang: Army Medical University (Third Military Medical University)
Yangyang Shang: Army Medical University (Third Military Medical University)
Hong Yang: Army Medical University (Third Military Medical University)
Yalan Song: Army Medical University (Third Military Medical University)
Shan Li: Army Medical University (Third Military Medical University)
Yusi Qin: Army Medical University (Third Military Medical University)
Jingyi Song: Army Medical University (Third Military Medical University)
Kang Chen: Army Medical University (Third Military Medical University)
Yang Liu: Army Medical University (Third Military Medical University)
Dinglin Zhang: Army Medical University (Third Military Medical University)
Lei Chen: Army Medical University (Third Military Medical University)

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The PD-1/PD-L1 pathway in mucosal immunity is currently actively explored and considered as a target for inflammatory bowel disease (IBD) treatment. However, systemic PD-L1 administration may cause unpredictable adverse effects due to immunosuppression. Here we show that reactive oxygen species (ROS)-responsive nanoparticles enhance the efficacy and safety of PD-L1 in a mouse colitis model. The nanoparticles control the accumulation and release of PD-L1 fused to Fc (PD-L1-Fc) at inflammatory sites in the colon. The nanotherapeutics shows superiority in alleviating inflammatory symptoms over systemic PD-L1-Fc administration and mitigates the adverse effects of PD-L1-Fc administration. The nanoparticles-formulated PD-L1-Fc affects production of proinflammatory and anti-inflammatory cytokines, attenuates the infiltration of macrophages, neutrophils, and dendritic cells, increases the frequencies of Treg, Th1 and Tfh cells, reshapes the gut microbiota composition; and increases short-chain fatty acid production. In summary, PD-L1-Fc-decorated nanoparticles may provide an effective and safe strategy for the targeted treatment of IBD.

Date: 2024
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DOI: 10.1038/s41467-024-46025-0

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