Polymersomes preventing brain infiltration of CD177+ neutrophils to mitigate hemorrhagic transformation post-tPA thrombolysis

Abstract

As an intravenous thrombolytic agent, tissue plasminogen activator (tPA) is limited by hemorrhagic transformation (HT) and a narrow therapeutic time window. Here we develop ROS-triggered polymersomes conjugated with fibrin-targeting CREKA peptide (CP) for tPA encapsulation. CP@tPA achieves efficient thrombosis targeting and enhanced thrombolytic efficacy, however, it has not been able to avert the occurrence of hemorrhage subsequent to thrombolysis. Building from our clinical discovery that stroke patients suffer from tPA-induced HT featured strong expression of CD177, recombinant CD177 protein (rCD177) was loaded into CP polymersomes (CP@rCD177) as nanomedicine and administrated prior to CP@tPA thrombolysis. rCD177 can be released in response to elevated ROS within the obstructed vessels, which binds to endothelial cells through interacting with CD31 and efficiently prevents the migration of CD177+ neutrophils into the brain parenchyma. The reduced CD177+ neutrophils suppress the generation of neutrophil extracellular traps (NETs), thereby dampening the inflammatory activation of microglia and ultimately improving the prognosis of HT. This innovative strategy presents a promising avenue for attenuating hemorrhagic complications post-thrombolysis.