Thrombin-Responsiveand Sequential Targeted Nanoplatformfor Synergistic Thrombolysis Therapy

Traditional thrombolytic therapy is limited by low specificity, uncontrollable bleeding complications, and secondary vascular re-embolism. To address this issue, we developed a thrombin-responsive and sequential targeted nanoplatform (MMSN-UK/TI@pep-Fuco) for efficient thrombolysis based on the attack-defense-protection integrated strategy. Herein, the multilevel mesoporous silica nanoparticle with multiple pore sizes was synthesized and modified with fucoidan (Fuco) using the compound peptide (pep) as a bridge to form multifunctional drug carriers MMSN@pep-Fuco. Then, urokinase (UK) and tirofiban (TI) were sequentially loaded into MMSN@pep-Fuco to obtain MMSN-UK/TI@pep-Fuco nano drug delivery systems (NDDS). In vitro and in vivo results demonstrated that MMSN-UK/TI@pep-Fuco maintained stability in the blood circulation to reduce bleeding risk (protection). Once arriving at the thrombus clots, Fuco facilitated NDDS identification and accumulation via P-selectin-mediated active targeting. Thereafter, Fuco coating on the surface of MMSN-UK/TI@pep-Fuco was shed in response to thrombin and then allowed quick release of UK from larger pores to achieve rapid thrombolysis (attack). Next, the exposed LS-MMSN/TI core NPs can continue colonizing at thrombolysis sites, and then TI loaded in smaller pores was released slowly and continuously to prevent re-embolization of blood vessels (defense). Pharmacodynamic results showed that the final thrombus blockage rate of the MMSN-UK/TI@pep-Fuco treatment group was only 4.87% with a relatively low bleeding risk. This nanoplatform provided a new strategy for the treatment of arterial thrombosis and related diseases.