Cell Communication-Mediated Selective Drug Delivery for Epitope-Specific Deletion of Alloreactive T Cells in Organ Transplant

Allogeneic grafts are vulnerable to the attack launched by host alloreactive T cells, which accounts primarily for allograft failure in the clinic. Conventional pharmacological intervention mainly involves broad-acting, nonspecific immunosuppressants that provide limited protection over the graft and may cause deleterious side effects due to insufficient allospecificity. Here, core-shell structured nanoparticles co-loaded with allogeneic antigen (Ag) and immunosuppressive agent Tacrolimus (Ag@FK506-NPs) are constructed. Dendritic cells (DCs) pulsed with Ag@FK506-NPs present alloantigenic epitopes on the cell surface as a bait to capture specific T cells, especially CD8+ T cells, for intercellular FK506 transfer and alloreactive T-cell deletion. Meanwhile, DCs are maintained in an immature tolerogenic state that induces the functional inactivation of recruited T cells. Compared with free FK506, the adoptive transfer of low immunosuppressant dose (25 000-fold lower) of Ag@FK506-NPs pulsed DCs is enough to yield a superior antirejection effect in a major histocompatibility complex-mismatched murine skin transplant model. Of note, due to the cell-cell communication conferred selective T-cell suppression, the recipient mouse is able to respond to the subsequent stimulation of an irrelevant Ag, indicating that off-target toxicity is bypassed. Overall, this work may address some of the limitations of current allograft therapeutics. In this work, core-shell structured nanoparticles co-loaded with allogeneic antigen (Ag) and immunosuppressive agent Tacrolimus (Ag@FK506-NPs) are constructed for sequential drug release and Ag epitope-specific recognition and deletion of recipient alloreactive T cells, which yields good antirejection effect without compromising the overall immunity in a murine fully major histocompatibility complex-mismatched skin allograft model.image