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Comprehensive sample analysis revealed dysregulation of FGL1\/LAG\u20103 and PD\u2010L1\/PD\u20101 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\u2010L1 (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\u2010L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD\u2010L1 on sEVs are specifically bound to their receptors, LAG\u20103 and PD\u20101 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\u2010dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8\n                    <jats:sup>+<\/jats:sup>\n                    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\u2010targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.\n                  <\/jats:p>","DOI":"10.1002\/advs.202102634","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T08:07:43Z","timestamp":1636099663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Engineered Small Extracellular Vesicles as a FGL1\/PD\u2010L1 Dual\u2010Targeting Delivery System for Alleviating Immune Rejection"],"prefix":"10.1002","volume":"9","author":[{"given":"Hsiang\u2010i","family":"Tsai","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences (Shenzhen) Sun Yat\u2010sen University  Shenzhen 518107 P. R. 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