<p>Organ transplantation is a crucial life-saving procedure for patients suffering from end-stage organ failure, yet it faces a global shortage. This scarcity not only impacts individual patients but also places strain on healthcare systems worldwide. However, the risk of rejection adds another layer of difficulty to this already intricate medical procedure. Herein, we present the design and synthesis of graft-targeting macrophage membrane coated nanoscale coordination polymers (dNCPs@MM), in which dexamethasone sodium phosphate (DEXp) serves as an effective immunosuppressive drug, Fe³⁺ acts as bridging ligands for coordination-driven self-assembly with cargo molecules, and macrophage membranes are utilized to reduce uptake by the immune system as well as a retarder to enhance the blood circulation time. The high drug loading, responsive release behavior and targeting capability of the obtained dNCPs@MM promote their biological performance. In a murine allogeneic heart transplantation model, dNCPs@MM exhibited remarkable efficacy in attenuating acute rejection at a low dosage, with a mean survival time of 14.7 days compared to 8.6 days for DEXp and 9.3 days for dNCPs treatment. At a high dosage, dNCPs@MM exhibited the ability to control established rejection by inducing exhaustion in both CD4⁺ and CD8⁺ T cell and preventing of alloreactive T cells from acquiring effector (CD44^hiCD62L⁻) functions. Moreover, while high doses of DEXp or dNCPs treatment led to significant adverse effects, the administration of dNCPs@MM demonstrates tolerable adverse effects even at high dosage levels. Therefore, dNCPs@MM exhibits promising potential for clinical application in addressing rejections in allografts and xenografts.</p> Graphical Abstract <p></p>