Upconversion Nanoparticles Regulated Urokinase And Nitric Oxide Dual-effective Nanoplatform For The Targeting Cooperated Therapy Of Thrombus And Anticoagulation

Thromboembolism is the leading cause of cardiovascular mortality.Currently,for the lack of targeting,short half-life,low bioavailability and high bleeding risk of the classical thrombolytic drugs,pharmacological thrombolysis is usually a slow process based on micro-pumping.Meanwhile,the high recurrence rate of thrombosis after thrombolytic therapy is a non-negligible problem.Therefore,long-term anticoagulation therapy after thrombolysis is equally essential.However,the long-term use of anticoagulants also increases the bleeding risk.In addition,frequently monitoring and regulating coagulation functions are also required during（and after）the process of thrombolysis.To address these issues,a targeted thrombolytic and anticoagulation nanoplatform（UCNP@m Si O₂-azo-Tirofiban-SNAP,UCATS-UK）was developed based on upconversion nanoparticles（UCNPs）that could convert 808 or 980 nm near-infrared（NIR）light into UV/blue light.First of all,the Nd³⁺doped UCNPs was synthesized by thermal decomposition method that could be excited by 808 nm NIR with better biological tissue penetration property.Azobenzene（azo）can be reversibly isomerized between cis and trans under visible and UV light irradiation,thus acting as a photo-responsive impeller for desirable light-controlled drug release.Then,the light-controlled drug release nanocarriers（UCNP@m Si O₂-azo,UCA）were constructed by coating mesoporous silica on the surface of UCNPs（UCNP@m Si O₂,UCM）and installing photomechanical azo inside the mesopores.Finally,the nitric oxide donor（SNAP）and platelet targeting molecule（Tirofiban）were modified on the surface of nanocarriers to obtain a multifunctional nanoplatform UCATS with targeted thrombolytic and anticoagulative capabilities.This nanoplatform could target and enrich in the thrombus site.Synergistic thrombolysis and anticoagulation therapy without increasing bleeding risk thus could be realized through the controlled release of urokinase（UK）and nitric oxide（NO）.Both in vitro and in vivo experiments have confirmed the excellent thrombolytic and anticoagulative capabilities of this multifunctional nanoplatform.Combined with the unique fluorescent imaging capability of UCNPs,this work is expected to contribute to the development of clinical thrombolysis therapy towards an integrated system of imaging,diagnosis and treatment.