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Nanocarriers are widely used for RA treatment; however, the targeted delivery and on\u2010demand release of multiple drugs remains challenging. Therefore, in this study, a dual\u2010sensitive polymer is developed using chondroitin sulfate (CS) for the co\u2010delivery of the cartilage repair agent, glucosamine (GlcN), and anti\u2010inflammatory drug, tofacitinib (Tof). In the joint cavity, acidic pH facilitates the cleavage of GlcN from CS polymer to repair the cartilage damage. Subsequently, macrophage uptake via CS\u2013CD44 binding and intracellular reactive oxygen species (ROS) mediate conversion of (methylsulfanyl)propylamine to a hydrophilic segment jointly triggered rapid Tof\/GlcN release via micelle disassembly. The combined effects of Tof, GlcN, and ROS depletion promote the M1\u2010to\u2010M2 polarization shift to attenuate inflammation. The synergistic effects of these agents against RA are confirmed in vitro and in vivo. Overall, the dual pH\/ROS\u2010sensitive CS nanoplatform simultaneously delivers GlcN and Tof, providing a multifunctional approach for RA treatment with synergistic drug effects.<\/jats:p>","DOI":"10.1002\/smll.202308520","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T01:26:25Z","timestamp":1704245185000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["pH and ROS Dual\u2010Sensitive Nanocarriers for the Targeted Co\u2010Delivery and On\u2010Demand Sequential Release of Tofacitinib and Glucosamine for Synergistic Rheumatoid Arthritis Treatment"],"prefix":"10.1002","volume":"20","author":[{"given":"Guo","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Orthopaedics and Traumatology Department of Orthopaedics Nanfang Hospital Southern Medical University  Guangzhou 510515 P. R. 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