An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases

Shenqiang Wang, Ying Zhang, Yanfang Wang, Yinxian Yang, Sheng Zhao, Tao Sheng, Yuqi Zhang, Zhen Gu (), Jinqiang Wang () and Jicheng Yu ()
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Shenqiang Wang: Zhejiang University
Ying Zhang: Zhejiang University
Yanfang Wang: Zhejiang University
Yinxian Yang: Zhejiang University
Sheng Zhao: Zhejiang University
Tao Sheng: Zhejiang University
Yuqi Zhang: Zhejiang University
Zhen Gu: Zhejiang University
Jinqiang Wang: Zhejiang University
Jicheng Yu: Zhejiang University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Immune checkpoints play key roles in maintaining self-tolerance. Targeted potentiation of the checkpoint molecule PD-L1 through in situ manipulation offers clinical promise for patients with autoimmune diseases. However, the therapeutic effects of these approaches are often compromised by limited specificity and inadequate expression. Here, we report a two-step dual-anchor coupling strategy for enhanced immobilization of PD-L1 on target endogenous cells by integrating bioorthogonal chemistry and physical insertion of the cell membrane. In both type 1 diabetes and rheumatoid arthritis mouse models, we demonstrate that this approach leads to elevated and sustained conjugation of PD-L1 on target cells, resulting in significant suppression of autoreactive immune cell activation, recruitment of regulatory T cells, and systematic reshaping of the immune environment. Furthermore, it restores glucose homeostasis in type 1 diabetic mice for over 100 days. This specific in situ bioengineering approach potentiates the functions of PD-L1 and represents its translational potential.

Date: 2023
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DOI: 10.1038/s41467-023-42725-1

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