Targeted Hybrid Theranostic Nanocarriers Enhance Thrombolytic Therapy via the Integration of Chemical and Physical Action.

Thrombolytic therapy remains hindered by short half-life, poor targeting, and bleeding risk of thrombolytic medicines (e.g., urokinase, UK). Here, we report a hybrid nanocarrier for targeted UK delivery with improved potency and reduced off-target toxicity. The tailored nanocarrier is made of gold nanoparticles (Au NPs) and multifunctional fused-albumin containing a targeting peptide that shows a high affinity with the overexpressed P-selectin on the membrane of the activated platelets in the thrombus site, demonstrating an impressive level of precision and efficiency in targeting. The enhancement of thrombolytic potency of the hybrid nanocarrier was proved in both cell and animal models. The targeting peptide-bearing albumin enabled prolonged systemic circulation and improved the deposition of UK in the thrombus. The albumin-capped Au NPs exhibited an amplified photothermal effect, inducing the clot disintegration and sensitizing the pharmacological action of UK through enhanced cargo penetration. Moreover, the Au NPs exhibited good X-ray attenuation ability, enabling kinetic monitoring of therapeutic efficacy through computed tomography (CT) imaging. Minimal hemolysis and histological injury confirmed safety of the hybrid nanocarrier. This work presents a versatile nanoplatform for integrated chemical and physical elimination of thrombi in a targeted manner, showing a high translation potential in clinical settings.