Functionalized Cell Membrane-coated Nanoparticles For Inducing Immune Tolerance Of Allogeneic Islet Graft

Type Ⅰ diabetes(T1DM)is a type of autoimmune disease that seriously threatens human health.Increasing the number of islets in patients through islet transplantation is currently an optimal treatment.However,allogeneic islet transplantation has a serious risk of immune rejection,and the need for life-long recipient immunosuppression may increase vulnerability to systemic infections and malignant tumors.How to develop new strategies for tolerance induction to avoid continuous recipient immunosuppression after islet transplantation,and to safely and efficiently prolong the survival of islets is the research focus.Effector T cells with high expression of Fasmolecule-can mediate transplant rejection as cytotoxic lymphocytes.And Fasis a member of the tumor necrosis factor receptor superfamily,which can rapidly induce cell apoptosis by bounding to Fasligand(FasL).Research indicates that the use of drug carriers to deliver FasL can inhibit the immune rejection of transplanted pancreatic islets by inducing effector T cell apoptosis.However,the present challenge is poor therapeutic effect of single delivery of FasL and insufficient safety of carrier materials.To address the above problems,we propose to use cell membranes with higher biological safety and pharmaceutical excipients PLGA(poly(lactic-co-glycolic acid))as carrier materials to jointly deliver FasL and immunosuppressive agents.Rapamycin is used to induce local immune tolerance of transplanted pancreatic islets.We first used PLGA to prepare drug-loaded nanoparticles(Rapa NP)encapsulating rapamycin(Rapamycin);then,the cell membrane directly expressing FasL was extracted and coated on the surface of Rapa NP to obtain FasL functionalized cell membrane-coated and Rapamycin loaded particles(FasL@Rapa NP).We proved that FasL@Rapa NP can effectively induce effector T cell apoptosis,thereby protecting islets from T cell attack in vitro.Subsequently,we constructed a T1DM mouse model with a C56BL/6 background,and co-transplanted islets from BALB/c mice and FasL@Rapa NP into T1DM mice.The results show that FasL@Rapa NP can induce local immune tolerance of allogeneic islet transplantation,effectively prolong the survival time of transplanted islets and treat T1DM without causing systemic immunosuppression.In summary,we have developed a safe and efficient functionalized cell membrane-camouflaged nanoparticles,which can effectively induce local immune tolerance,provide new research approach for transplant immune rejection therapy,and have a certain transformational prospect.