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A two\u2010pronged strategy for the regulation of intracellular\/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1\/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in \u201ctwo\u2010in\u2010one\u201d nanocarriers (NAHA\u2010CaP\/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (\u224890%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro\u2010chondrogenic TGF\u2010<jats:italic>\u03b2<\/jats:italic>1 mRNA (\u22481.3\u2010fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti\u2010inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid\u2010induced early and late OA mouse models and a surgical destabilization of medial meniscus\u2010induced OA rat model. Therefore, the siCA9 and NO scavenger \u201ctwo\u2010in\u2010one\u201d delivery system is a potential and efficient strategy for progressive OA treatment.<\/jats:p>","DOI":"10.1002\/advs.202207490","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T07:40:47Z","timestamp":1675755647000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6479-6595","authenticated-orcid":false,"given":"Yi","family":"Yan","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 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