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

Adv Sci (Weinh). 2022 Jan;9(3):e2102634. doi: 10.1002/advs.202102634. Epub 2021 Nov 5.

Abstract

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.

Keywords: FGL1; Immunological rejection; Immunosuppressant; PD-L1; Small extracellular vesicles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / metabolism
  • Disease Models, Animal
  • Extracellular Vesicles / metabolism*
  • Fibrinogen / genetics*
  • Fibrinogen / metabolism
  • Graft Rejection / genetics
  • Graft Rejection / prevention & control*
  • Heart Transplantation
  • Humans
  • Immunosuppressive Agents / metabolism
  • Immunosuppressive Agents / therapeutic use*
  • Kidney Transplantation
  • Mesenchymal Stem Cells
  • Mice
  • Transplant Recipients

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • FGL1 protein, human
  • Fgl1 protein, mouse
  • Immunosuppressive Agents
  • Fibrinogen

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