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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.


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Engineered protein and Jakinib nanoplatform with extraordinary rheumatoid arthritis treatment

Show Author's information Yuanxin Li1,2Bo Li3Gang Wang4Juanjuan Su5Yilin Qiao3Chao Ma3Fan Wang1Jian Zhu6( )Jingjing Li1( )Hongjie Zhang1,3Kai Liu3( )Huji Xu4( )
State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
University of Science and Technology of China, Hefei 230026, China
Engineering Research Center of Advanced Rare Earth Materials, (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
School of Clinical Medicine, Tsinghua University, Beijing 100084, China
College of Materials Science and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China
First Medical Centre, Chinese PLA General Hospital, Beijing 100853, China

Abstract

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.

Keywords: controlled release, rheumatoid arthritis, nanocarrier, engineered protein, bioefficacy

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Publication history
Copyright
Acknowledgements

Publication history

Received: 25 March 2023
Revised: 13 May 2023
Accepted: 15 May 2023
Published: 10 June 2023
Issue date: August 2023

Copyright

© Tsinghua University Press 2023

Acknowledgements

Acknowledgements

This research was 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), 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 China, and with the approval of the Institutional Animal Care and Use Committee of the Animal Experiment Center of Jilin University (No. PZPX20180929070).

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