Macrophage Membrane Coated Dexamethasone-Fe3+ Based Nanoscale Coordination Polymers For Organ Transplantation

Organ transplantation has become the main therapy for patients with end-stage diseases,and long-term immunosuppressive treatment is required after transplantation for preventing graft rejection.Glucocorticoids（GCs）as a kind of effective anti-inflammatory and anti-rejection drug,has been widely used in the perioperative period of organ transplantation surgery.But the systemic side effects of long-term use limit their use.Herein,there is an urgent need to develop new strategies to improve the use of traditional immunosuppressants to improve the survival rate of transplant patients.Nanotechnology has received much attention in the development of novel therapies for tumors because of its unique size and physicochemical properties.Nanotechnology has received much attention in the development of novel therapies for tumors because of its unique size and physicochemical properties.Nanotechnology can be used to improve the pharmacokinetics and targeting ability of small molecule drugs.In addition,cell membranebased nanotechnology is an emerging nano-engineering technology in recent years.This technology allows the use of natural cell membranes to modify synthetic nanomaterials and give the nanoparticles part of the functions derived from the original cells.In this study,a nanoscale organic-metal coordination polymer（d NCPs）was constructed based on the coordination of dexamethasone sodium phosphate（DEXp）with iron ions(Fe³⁺).Extraction of macrophage membrane coating d NCPs nanoparticles and synthesis of a new stable and homogeneous macrophage membrane-mimetic nano-coordination polymer（d NCPs@MM）.d NCPs@MM has very high drug delivery efficiency and does not require nanocarriers.In vitro drug release assays have demonstrated that d NCPs@MM have acidsensitive and suggesting a slow-releasing property of d NCPs@MM in an inflammatory environment.And the biosafety properties of d NCPs were also preliminarily confirmed.Ischemia-reperfusion injury（IRI）is one of the most important factors affecting posttransplant recipient complications and mortality.In the second part of the study,the escape function from macrophage uptaking and inflammatory targeting ability of d NCPs@MM on macrophage phagocytosis in vitro were first confirmed using flow cytometry and confocal techniques.The pharmacokinetics and biodistribution of d NCPs@MM in organisms were further investigated by IVIS.The d NCPs@MM nanoparticles can stay in the system circulation for a longer time than water-soluble small molecule drugs.In a liver IRI model constructed in C57BL/6 mice,it was found that d NCPs@MM nanodrugs were confirmed to more significantly improve hepatic biochemical AST and ALT levels and reduce the necrotic area of the liver after IRI by pre-administration of d NCPs@MM nanodrugs intravenously before ischemia than DEXp.In liver IRI model constructed in C57BL/6 mice,it was found that with preadministration with d NCPs@MM could significantly reduce the hepatic AST and ALT levels andl iver necrotic area after IRI.Meanwhile,TUNEL staining and the expression of apoptosis proteins Cleaved-caspase-3and Bcl-2/Bax protein also indicated that d NCPs@MM nanoparticles could significantly inhibit IRI-induced hepatocyte apoptosis.In addition,d NCPs@MM could attenuate the IRI-induced inflammatory response by inhibiting the activation of NF-κB signaling pathway,down-regulate the secretion of inflammatory cytokines,and reduce the infiltration of inflammatory cells in liver tissues.Taken together,the results suggest that d NCPs@MM has better pharmacokinetic and livertargeting properties than conventional DEXp,bringing a stronger protective effect.In the third part of the study,we first constructed a mouse allogeneic heart transplantation model using C57BL/6 and BALB/c mice to investigate the role of d NCPs@MM in transplant rejection.Pharmacokinetic and biodistribution studies of d NCPs@MM nanodrugs in a mouse heart transplantation model demonstrated the ability of d NCPs@MM targeting the spleen and graft organs in the transplantation model.Compared to conventional DEXp treatment,d NCPs@MM significantly extends the survival of grafts through inducing immune suppression,thus reducing the inflammatory response of the recipients.Finally,this part of the study also explored the application of this nanoparticle formulation with GCs-related side effects.The results showed that d NCPs@MM treatment significantly reduced the effects of DEXp on weight loss,blood glucose and osteoporosis in mice compared to the conventional DEXp treatment regimen.The third part of the study shows that d NCPs@MM has the ability of targetting spleen and graft in allograft mice,which can significantly improve the effect of anti-rejection treatment of DEXp and reduce the side effects.In conclusion,this study synthesized a novel biomimetic nanomedicine d NCPs@MM using macrophage membrane coated DEXp and Fe³⁺-assembled nanoparticles d NCPs.This is a morphologically homogeneous and stable nanoparticle with long circulation effect and inflammation targeting ability.This nanomedicine is highly biocompatible and be able to release drug in response to environment of inflammation,which can effectively reduce organ ischemia reperfusion injury,and its excellent anti-rejection effect has been verified in transplantation models.Our study might provide a new strategy for safe and effective targeting treatment of organ transplantation or other related inflammatory diseases.