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

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 thromboinflammation 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.