Rheumatoid arthritis(RA)is a relatively common inflammatory disease that affects the synovial tissue,eventually results in joints destruction and even long-term disability.Although Janus kinase inhibitors(Jakinibs)sho...Rheumatoid arthritis(RA)is a relatively common inflammatory disease that affects the synovial tissue,eventually results in joints destruction and even long-term disability.Although Janus kinase inhibitors(Jakinibs)show a rapid efficacy and are becoming the most successful agents in RA therapy,high dosing at frequent interval and severe toxicities cannot be avoided.Here,we developed a new type of fully compatible nanocarriers based on recombinant chimeric proteins with outstanding controlled release of upadacitinib.In addition,the fluorescent protein component of the nanocarriers enabled noninvasive fluorescence imaging of RA lesions,thus allowing real-time detection of RA therapy.Using rat models,the nanotherapeutic is shown to be superior to free upadacitinib,as indicated by extended circulation time and sustained bioefficacy.Strikingly,this nanosystem possesses an ultralong half-life of 45 h and a bioavailability of 4-times higher than pristine upadacitinib,thus extending the dosing interval from one day to 2 weeks.Side effects such as over-immunosuppression and leukocyte levels reduction were significantly mitigated.This smart strategy boosts efficacy,safety and visuality of Jakinibs in RA therapy,and potently enables customized designs of nanoplatforms for other therapeutics.展开更多
基金supported by the National Key R&D Program of China(Nos.2022YFA0913200,2021YFF0701800,2022YFF0710000,and 2020YFA0908900)the National Natural Science Foundation of China(Nos.22107097,22020102003,22277064,82272161,and 22125701)+1 种基金Tsinghua University Spring Breeze Fund grant(No.2021Z99CFZ005),and the Youth Innovation Promotion Association of CAS(No.2021226)All animal experiments were conducted in compliance with the Animal Management Rules of the Ministry of Health of the People's Republic of Chinawith the approval of the Institutional Animal Care and Use Committee of the Animal Experiment Center of Jilin University(No.PZPX20180929070).
文摘Rheumatoid arthritis(RA)is a relatively common inflammatory disease that affects the synovial tissue,eventually results in joints destruction and even long-term disability.Although Janus kinase inhibitors(Jakinibs)show a rapid efficacy and are becoming the most successful agents in RA therapy,high dosing at frequent interval and severe toxicities cannot be avoided.Here,we developed a new type of fully compatible nanocarriers based on recombinant chimeric proteins with outstanding controlled release of upadacitinib.In addition,the fluorescent protein component of the nanocarriers enabled noninvasive fluorescence imaging of RA lesions,thus allowing real-time detection of RA therapy.Using rat models,the nanotherapeutic is shown to be superior to free upadacitinib,as indicated by extended circulation time and sustained bioefficacy.Strikingly,this nanosystem possesses an ultralong half-life of 45 h and a bioavailability of 4-times higher than pristine upadacitinib,thus extending the dosing interval from one day to 2 weeks.Side effects such as over-immunosuppression and leukocyte levels reduction were significantly mitigated.This smart strategy boosts efficacy,safety and visuality of Jakinibs in RA therapy,and potently enables customized designs of nanoplatforms for other therapeutics.
