Biomimetic sequential targeted nanoplatform for synergistic thrombolysis in ischemic stroke

Conventional thrombolytic drugs for vascular blockage such as tissue plasminogen activator (tPA) are challenged by the low bioavailability, off-target side effects and limited penetration in thrombi, leading to delayed recanalization. Herein, we developed a sequential targeted nanoplatform for efficient thrombolysis based on the thrombolysis-neuroprotection integrated strategy. The mesoporous silica layer-modified upconversion nanoparticle (UCNP) was loaded with the nitric oxide (NO) donors (BNN6), further coating platelet membranes (PMs) on the surface of UCNP. tPA was conjugated onto PMs using the MMP9-responsive peptide as a linker to form a multifunctional drug carrier of UCNP/BNN6@PM-tPA. The proposed drug carrier maintained stability in the blood circulation to reduce bleeding risk (protection), facilitating it colonizing at the thrombus clots. MMP-9 triggered the release of tPA to realize rapid thrombolysis (attack), whereas continuous NO release from NIR-irradiated BNN6 acted to prevent vascular re-embolization (defense). In vitro and in vivo evaluation revealed that UCNP/BNN6@PM-tPA enables thrombus-homing accumulation, fluorescence imaging-guided thrombolysis, and NO mediated prevention of thrombosis recurrence, displaying favorable therapeutic outcomes with low bleeding risk. This study offers a facile, safe, and effective way towards the clinical treatment of thrombosis and ischemic stroke.