Honeybee-mimicking microenvironment-responsive theranostic nanovesicles for enhanced magnetic resonance imaging and...

Developing a theranostic system integrating specific thrombus targeting, microenvironment-responsive drug release and imaging remains challenging. Inspired by "honeybees finding nectars", we first designed a honeybee-mimicking nanovesicle (denoted as tPA@THPTN), which mimics honeybees' ability to seek (target), to respond (release drug in the target microenvironment), and to report (provide real-time location feedback) for targeted delivery of tissue plasminogen activator (tPA) to enhance thrombolytic therapy. This biomimetic nanovesicle was constructed through simple self-assembly with thioketal linker-containing lipids for microenvironment response, decorated with fibrinogen-derived peptides for targeting, and surface-coated with 2,2,6,6-tetramethylpiperidin-1-oxyl for enhanced magnetic resonance (MR) contrast. In vitro static and microfluidic studies confirmed the specific binding to activated platelets and efficient thrombus targeting under a flow condition. Efficient thrombus microenvironment response and triggered tPA release was demonstrated, thus leading to effective thrombolysis under both static and flow conditions. Intravenous administration in vivo enabled prolonged circulation, enhanced thrombus accumulation and MR imaging. In a rat carotid thrombosis model, tPA@THPTN outperformed free tPA and non-targeted controls, achieving complete clot dissolution in 120 min with minimal hemorrhage risk. This biomimetic platform offers a potent theranostic strategy for thrombosis.