Biomimetic ultra-small copper nanoparticles for brain targeting and precise treatment of ischemic stroke

Ischemic stroke (IS) remains a major cause of mortality and disability worldwide, largely due to difficulty in drug delivery to ischemic sites and complex pathophysiological mechanisms involving multiple cells. In this study, we developed a biomimetic nanodecoy by coating ultra-small copper nanoparticles (CuNPs) with M2 macrophage membrane (M2MPM) and platelet membranes (PLM), forming CuNPs@[PLM-M2MPM]NVs engineered to improve the treatment of IS. CuNPs@[PLM-M2MPM]NVs achieved targeting to the infarcted region via mimicking of natural platelet adhesion and inflammation-homing effects, allowing CuNPs to migrate toward and accumulate in inflamed ischemic brain regions. In the meantime, CuNPs@[PLM-M2MPM]NVs effectively scavenged reactive oxygen species (ROS) leveraging multi-enzyme cascade activities of CuNPs. Furthermore, CuNPs@[PLM-M2MPM]NVs neutralized free pro-inflammatory cytokines by means of the unique binding properties of M2MPM, creating the anti-inflammatory microenvironment. In vivo findings revealed that CuNPs@[PLM-M2MPM]NVs markedly alleviated IS induced injury in a rat middle cerebral artery occlusion reperfusion (MCAO/R) model.