Functionalized cell membrane-coated nanoparticles induce local immune tolerance for durable survival of allogeneic islet grafts

Allogeneic islet transplantation is a promising therapeutic strategy for type 1 diabetes (T1D). However, establishing durable immune tolerance to protect engrafted islets without systemic immunosuppression remains a major challenge. In this study, we develop functionalized cell membrane-coated nanoparticles to induce local immune tolerance and achieve long-term islet graft protection. These nanoparticles, termed FasL@Rapa NPs, are engineered by coating rapamycin-loaded polymeric cores with cell membranes expressing Fas ligand (FasL). Upon co-transplantation with allogeneic islets into the subrenal capsule of T1D mice, FasL@Rapa NPs promote apoptosis of autoreactive effector T cells <i>via</i> FasL-Fas interaction, and simultaneously expand the population of regulatory T cells <i>via</i> rapamycin-mediated immune regulation within the islet grafts. This dual immunomodulatory action successfully establishes local immune tolerance, enabling prolonged graft survival and sustained insulin secretion, thereby restoring normoglycemia in diabetic mice. This study presents a promising approach to prevent transplant rejection without the risks associated with systemic immunosuppression.