Sonodynamic and Bioorthogonal Sonocatalytic Thrombotic Therapy Based on AIE Cationic Tetranuclear Ir(III) Complex Nanoplatform Guided by NIR-Chemiluminescence Imaging.

Abstract

Non-invasive thrombolytic strategies include photothermal therapy (PTT), photodynamic therapy (PDT) and sonodynamic therapy (SDT). The development of PTT and PDT is impeded by the limited tissue penetration depth of the light source. SDT is a promising method due to the deeper tissue penetration and site-specific features of ultrasound; however, the scarcity of efficient sonosensitizers has constrained its clinical use. Herein, ultrasound-triggered nanoparticles (NPs), named Ir-4@S-R NPs, achieve a sonodynamic thrombolytic, bioorthogonal sonocatalytic reaction, with chemiluminescence (CL) imaging in the thrombus. An Ir(III) complex, named Ir-4, which has aggregation induced emission (AIE), combined with a hydrogen sulfide donor, named H₂S-N₃, provide the nanoplatform which is modified with the peptide c(RGDfC) to target the thrombus. This supramolecular assembly successfully integrates: i) thrombosis detection based on near-infrared (NIR) chemiluminescence imaging, ii) sonodynamic thrombus therapy and iii) release of hydrogen sulfide for anti-inflammatory action. Ir-4@S-R NPs emit long-lasting NIR CL triggered by endogenous ONOO^- and achieve 12 mm deep tissue penetration. Blood clots are effectively removed and blood flow is almost fully restored in mouse carotid thrombus and rat femoral vein models. The work demonstrates a new integrated strategy for diagnosing and treating life-threatening diseases caused by thrombusotic disorders.