Abstract
There is an urgent need for developing new immunosuppressive agents due to the toxicity of long-term use of broad immunosuppressive agents post organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG-3 and PD-L1/PD-1 immune checkpoints in allogenic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, we developed a bioengineering strategy 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 enriched FGL1/PD-L1 expression, but also maintained the immunomodulatory properties of unmodified MSC sEVs. Next, we confirmed that FGL1 and PD-L1 on sEVs specifically bound to their receptors LAG-3 and PD-1 on target cells. Importantly, FP sEVs significantly inhibited T cell activation and proliferation in vitro and in a heart allograft model. Furthermore, FP sEVs encapsulated with low-dose FK506 (FP sEVs@FK506) exerted 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 has the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.
Competing Interest Statement
The authors have declared no competing interest.