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

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.

An Overview of Current Research on Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Bibliometric Analysis From 2009 to 2021

“…Engineered EVs are obtained by genetic modification of donor cells or chemical modification of EVs for targeted delivery, increasing local concentrations at diseased sites, reducing toxicity and side effects, and maximizing therapeutic efficacy (Liang et al, 2021). Tsai HI et al modified MSCs to obtain engineered EVs expressing FGL1 and PD-L1 on the membrane surface, which could target and bind to LAG-3 and PD-1 on the surface of T cells, thereby inhibiting T cell activation, and inducing immune tolerance in a heart allograft model (Tsai et al, 2022). The multidisciplinary combination helped to broaden the research horizon, overcome the research challenges, and lay the foundation for clinical translation in the field of MSC-EVs.…”

Small Extracellular Vesicles Derived From MSCs Have Immunomodulatory Effects to Enhance Delivery of ASO-210 for Psoriasis Treatment

“…For example, MSC-derived sEVs have been reported to have therapeutic effects in GvHD ( Zhou et al, 2020 ) and autoimmune diseases, including the induction of tissue regeneration ( Chen et al, 2008 ), immunosuppression, and anti-inflammatory properties ( Jin-Hee et al, 2018 ). MSC-sEVs can also be modified to display multiple immunomodulatory molecules on the membrane surface to potentiate their immunosuppressive potential ( Tsai et al, 2021 ). These favorable characteristics underscore the potential of MSC-sEVs as a unique drug delivery vehicle to treat psoriasis.…”

Research progress of engineered mesenchymal stem cells and their derived exosomes and their application in autoimmune/inflammatory diseases

“…In addition, Hsiang-I et al found that the receptors for the negative immune regulators PD-1 and LAG-3 were significantly elevated on T lymphocytes in clinical samples from kidney transplant patients and in heart transplant model mice. Therefore, they constructed PD-L1/FGL1 double-expressing MSC-exos by lentiviral vector, and both in vitro cell experiments and in vivo animal experiments confirmed that PD-L1/FGL1 double-expressing MSC-exos had stronger resistance to organ transplantation immune rejection [ 58 ]. Baculovirus is minimally virulent, neither replicates nor integrates into the host genome and is capable of transduction with high efficiency [ 59 ].…”