title: Microvesicle-mediated delivery of transforming growth factor β1 siRNA for the suppression of tumor growth in mice.
abstract: Cell-derived microvesicles (MVs) have been recently shown as an efficient carrier to deliver small RNAs into the target cells. In the present study, we characterized the inhibitory effect of TGF-β1 siRNA delivered by mouse fibroblast L929 cell-derived MVs (L929 MVs) on the growth and metastasis of murine sarcomas 180 cells both in vitro and in vivo. We found that, comparing to the same concentration of free TGF-β1 siRNA, TGF-β1 siRNA delivered by L929 MVs much more efficiently decreased the level of TGF-β1 in the recipient tumor cells. Functionally, MVs containing TGF-β1 siRNA significantly decreased the viability and migration of sarcomas 180 cells and promoted the apoptosis of tumor cells. Co-immunoprecipitation with Argonaute 2 (AGO2) via anti-AGO2 antibody indicated that the majority of TGF-β1 siRNA in the MVs were associated with AGO2 complex. A tumor implantation mouse model further showed that intravenous injection of TGF-β1 siRNA-containing MVs strongly suppressed TGF-β1 expression and TGF-β1 signaling downstream in the implanted tumor cells, and thus inhibited the growth and lung metastases of tumor cells. In conclusion, our results collectively demonstrate that the delivery of therapeutic TGF-β1 siRNA by cell-derived MVs provides an effective strategy to control tumor cell growth and metastasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Li
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China.
authors.forename: Dihan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China.
authors.forename: Xihan
authors.initials: X
authors.lastname: Li
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China. Electronic address: hongweigu@nju.edu.cn.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gu
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China. Electronic address: cyzhang@nju.edu.cn.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, School of Life Sciences, Nanjing, Jiangsu 210093, China. Electronic address: kzen@nju.edu.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
mesh_terms: D000818:Animals; D017209:Apoptosis; D060565:Argonaute Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018014:Gene Transfer Techniques; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D053835:Unilamellar Liposomes / Q000737:chemistry*
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D053835:Unilamellar Liposomes
keywords: Microvesicle; Systemic delivery; TGF-β1; Tumor therapy; siRNA