Multivalent Bi‐Specific Nanoerythrosomes: A Two‐Birds‐One‐Stone Approach to Combine Homologous and Active Targeting for Effective Thrombolysis

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Combining homologous targeting and active targeting to a thrombus is highly desirable in targeted thrombolytic therapy. Here, we report a multivalent bi-specific nanoerythrosome for thrombus-targeted delivery of tissue plasminogen activator (tPA) (denoted as mBiNE@tPA) to achieve effective thrombolysis. This bio-inspired delivery system was fabricated to exploit two main thrombus components by utilizing the natural erythrocyte membrane for homologous targeting to a thrombus and fibrinogen-derived cyclic arginine-glycine-aspartic acid (cRGD) motifs for active targeting to activated platelets. mBiNE@tPA maintained tPA's activity during extended circulation. Its preferential thrombus accumulation, enhanced thrombus penetration, and triggered tPA release locally through the combined homologous and active thrombus targeting were demonstrated. Efficient and selective fibrinolysis and thrombolysis both in vitro and in vivo were achieved, leading to effective vascular recanalization with minimal hemorrhagic risks in mice. Through the combined experimental and computational work, mBiNE@tPA exhibited superior thrombolytic capabilities over formulations with single or no targeting specificity and free tPA. This nanoerythrosome represents a promising platform for targeted therapies.