Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection

作者：Tsai, Hsiang-, I; Wu, Yingyi; Liu, Xiaoyan; Xu, Zhanxue; Liu, Longshan; Wang, Changxi; Zhang, Huanxi; Huang, Yisheng; Wang, Linglu; Zhang, Weixian; Su, Dandan; Khan, Fahim Ullah; Zhu, Xiaofeng; Yang, Rongya; Pang, Yuxin; Eriksson, John E.; Zhu, Haitao; Wang, Dongqing; Jia, Bo^*; Cheng, Fang^*; Chen, Hongbo^*

来源：Advanced Science, 2022, 9(3): 2102634.

DOI：10.1002/advs.202102634

• FGL1
• Immunological rejection
• Immunosuppressant
• PD-L1
• Small extracellular vesicles

There is an urgent need for developing new immunosuppressive agents due to the toxicity of long-term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG-3 and PD-L1/PD-1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD-L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD-L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD-L1 on sEVs are specifically bound to their receptors, LAG-3 and PD-1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low-dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8(+) T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual-targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.

• 单位
  中山大学; 广东药学院; 南方医科大学; 江苏大学; 1