Thrombin-responsive engineered nanoexcavator with full-thickness infiltration capability for pharmaceutical-free deep venous thrombosis theranostics

Abstract

Although nanotechnology has shown great promise for treating multiple vascular diseases in recent years, simultaneous noninvasive detection and efficient dissolution of deep venous thrombosis (DVT) still remains challenging. In particular, long blockage areas and large thrombus thicknesses in DVT cause enormous difficulties for site-specific deep-seated thrombus theranostics. Therefore, based on the unique components of DVT, the novel concept of a thrombin-responsive full-thickness infiltration nonpharmaceutical nanoplatform for DVT theranostics is proposed here. The penetration depth is innovatively enhanced with efficient targeting and accumulation in the whole thrombi. Herein, we report a thrombin-responsive phase-transition liposome incorporating a liquid perfluoropentane (PFP) core and modified with two binding peptides, activatable cell-penetrating peptide (ACPP) and fibrin-binding ligand (FTP), which contribute to efficient liposome targeting and accumulation within the thrombi. This targeted nanoplatform is constructed to dig out the thrombus with the assistance of low-intensity focused ultrasound (LIFU), performing the destructive function of an excavator via an acoustic droplet vaporization effect (acting as a “nanoexcavator” system), which can activate and vaporize into microbubbles to enhance LIFU efficacy. The resulting microbubbles enable real-time monitoring of the therapeutic process with ultrasound imaging and high performance photoacoustic imaging after loading DIR. This non-invasive nonpharmaceutical thrombolytic strategy is an improvement over existing clinical methods without systemic side effects.