2. Academic Validation
  3. An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases

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

  • Nat Commun. 2023 Oct 31;14(1):6953. doi: 10.1038/s41467-023-42725-1.
Shenqiang Wang 1,  Ying Zhang 1,  Yanfang Wang 1,  Yinxian Yang 1,  Sheng Zhao 1,  Tao Sheng 1,  Yuqi Zhang 1 2 3,  Zhen Gu 4 5 6 7 8 9,  Jinqiang Wang 10 11 12 13,  Jicheng Yu 14 15 16 17 18
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 Department of Burns and Wound Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
  • 3 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China.
  • 4 Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. guzhen@zju.edu.cn.
  • 5 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. guzhen@zju.edu.cn.
  • 6 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China. guzhen@zju.edu.cn.
  • 7 Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. guzhen@zju.edu.cn.
  • 8 Jinhua Institute of Zhejiang University, Jinhua, 321299, China. guzhen@zju.edu.cn.
  • 9 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China. guzhen@zju.edu.cn.
  • 10 Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. jinqiang_wang@zju.edu.cn.
  • 11 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. jinqiang_wang@zju.edu.cn.
  • 12 Jinhua Institute of Zhejiang University, Jinhua, 321299, China. jinqiang_wang@zju.edu.cn.
  • 13 Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China. jinqiang_wang@zju.edu.cn.
  • 14 Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. yujicheng@zju.edu.cn.
  • 15 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. yujicheng@zju.edu.cn.
  • 16 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China. yujicheng@zju.edu.cn.
  • 17 Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. yujicheng@zju.edu.cn.
  • 18 Jinhua Institute of Zhejiang University, Jinhua, 321299, China. yujicheng@zju.edu.cn.
PMID: 37907476 DOI: 10.1038/s41467-023-42725-1
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.

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