Engineered small extracellular vesicles as a FGL1/PD-L1 dual-targeting delivery system for alleviating immune rejection

Tsai, H.-i.; Wu, Y.; Liu, X.; Xu, Z.; Liu, L.; Huang, Y.; Wang, L.; Zhang, W.; Zhang, H.; Su, D.; Khan, F. U.; Wang, C.; Eriksson, J. E.; Jia, B.; Cheng, F.; Chen, H.

doi:10.1101/2021.06.14.448282

bioRxiv · 10.1101/2021.06.14.448282

Engineered small extracellular vesicles as a FGL1/PD-L1 dual-targeting delivery system for alleviating immune rejection

Tsai, H.-i.·Wu, Y.·Liu, X.·Xu, Z.·Liu, L.·Huang, Y.·Wang, L.·Zhang, W.·Zhang, H.·Su, D.·Khan, F. U.·Wang, C.·Eriksson, J. E.·Jia, B.·Cheng, F.·Chen, H.

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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 allogeneic 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 were 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 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 have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.

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Tsai, H.-i., Wu, Y., Liu, X., Xu, Z., Liu, L., Huang, Y., Wang, L., Zhang, W., Zhang, H., Su, D., Khan, F. U., Wang, C., Eriksson, J. E., Jia, B., Cheng, F., Chen, H.. 2021-06-15. Engineered small extracellular vesicles as a FGL1/PD-L1 dual-targeting delivery system for alleviating immune rejection. https://doi.org/10.1101/2021.06.14.448282

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