Relieving thrombo-inflammation with acid-triggered polymersomes toward ischemic stroke therapy

Abstract

In acute ischemic stroke, neutrophils contribute to ischemia-reperfusion injury through producing neutrophil extracellular traps (NETs), which promote the interaction of platelets and neutrophils to elicit thrombo-inflammation and facilitate further infarct development. As the primary degrader of NETs, DNase 1 is restricted by easy deactivation and low efficiency to enrich in the ischemic brain. Herein, a pH-triggered polymersome nanoplatform is fabricated for enhanced brain delivery of DNase 1 to relieve ischemic stroke-related thrombo-inflammation. The polymersomes can efficiently disintegrate upon acidic microenvironment, releasing DNase 1 to clear NETs, which disrupt the thrombus skeleton structure to inhibit microthrombosis. Furthermore, DNase 1 can decrease the stability of histones in NETs to prevent platelet activation through TLR4 pathway, which in turn downregulate HMGB-1 to avoid NETs formation. As a result, the platelets and neutrophils aggregates can be effectively reduced simultaneously through NETs decomposition and inhibition of platelet activation. The acid-triggered polymersomes may present a promising strategy for ischemic stroke therapy.