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For efficient RA therapy, here a multifunctional nanoplatform is presented based on generation 5 (G5) poly(amidoamine) dendrimer\u2010entrapped gold nanoparticles (Au DENPs) to achieve co\u2010delivery of antioxidant alpha\u2010tocopheryl succinate (\u03b1\u2010TOS) and anti\u2010inflammatory anti\u2010TNF\u2010\u03b1 siRNA to macrophage cells. G5 dendrimers with amine termini are sequentially functionalized with 1,3\u2010propane sultone (1,3\u2010PS), \u03b1\u2010TOS through a polyethylene glycol (PEG) spacer, and PEGylated folic acid (FA), and subsequently entrapped with Au NPs. The generated functional Au DENPs exhibit desired cytocompatibility, zwitterion\u2010rendered antifouling property, and FA\u2010mediated targeting specificity, enabling serum\u2010enhanced siRNA delivery to M1\u2010type macrophage cells. Meanwhile, the attached \u03b1\u2010TOS affords enhanced oxidation resistance of macrophage cells. In vivo investigation shows that the treatment of a collagen\u2010induced arthritis mouse model using \u03b1\u2010TOS\u2010modified Au DENPs\/TNF\u2010\u03b1 siRNA polyplexes can achieve excellent combination therapy effect in inflammatory cytokines downregulation of RA lesion and bone erosions. The therapeutic efficacy is also supported by 3D micro\u2010computed tomography analysis and TNF\u2010\u03b1 cytokine reduction of RA lesion joints in the mRNA, protein, and histology levels. The created multifunctional nanoplatform may be employed in antioxidative and anti\u2010inflammatory combination therapy of RA.<\/jats:p>","DOI":"10.1002\/smll.202005661","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T09:45:58Z","timestamp":1605692758000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":106,"title":["Targeted Combination of Antioxidative and Anti\u2010Inflammatory Therapy of Rheumatoid Arthritis using Multifunctional Dendrimer\u2010Entrapped Gold Nanoparticles as a Platform"],"prefix":"10.1002","volume":"16","author":[{"given":"Jin","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory for Modification of Chemical Fibers and Polymer Materials International Joint Laboratory for Advanced Fiber and Low\u2010Dimension Materials College of Chemistry, Chemical Engineering and Biotechnology Donghua University  Shanghai 201620 P. R. China"}]},{"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Modification of Chemical Fibers and Polymer Materials International Joint Laboratory for Advanced Fiber and Low\u2010Dimension Materials College of Chemistry, Chemical Engineering and Biotechnology Donghua University  Shanghai 201620 P. R. China"}]},{"given":"Xiaoying","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Modification of Chemical Fibers and Polymer Materials International Joint Laboratory for Advanced Fiber and Low\u2010Dimension Materials College of Chemistry, Chemical Engineering and Biotechnology Donghua University  Shanghai 201620 P. R. 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China"}]},{"given":"Mingwu","family":"Shen","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Modification of Chemical Fibers and Polymer Materials International Joint Laboratory for Advanced Fiber and Low\u2010Dimension Materials College of Chemistry, Chemical Engineering and Biotechnology Donghua University  Shanghai 201620 P. R. China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6785-6645","authenticated-orcid":false,"given":"Xiangyang","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Modification of Chemical Fibers and Polymer Materials International Joint Laboratory for Advanced Fiber and Low\u2010Dimension Materials College of Chemistry, Chemical Engineering and Biotechnology Donghua University  Shanghai 201620 P. R. 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