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Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR\u2010199a\u20105p or IGF2BP2 and by the ability of cPKM to stabilize STMN1\/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co\u2010loading of siRNA against cPKM (si\u2010cPKM) and paclitaxel (PTX) is developed. The siRNA\/PTX co\u2010loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si\u2010cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment.<\/jats:p>","DOI":"10.1002\/advs.202303814","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T05:11:57Z","timestamp":1696396317000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["A Novel Trojan Horse Nanotherapy Strategy Targeting the cPKM\u2010STMN1\/TGFB1 Axis for Effective Treatment of Intrahepatic Cholangiocarcinoma"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1770-6208","authenticated-orcid":false,"given":"Zhi\u2010Wen","family":"Chen","sequence":"first","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University  Fuzhou 350001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng\u2010Ping","family":"Kang","sequence":"additional","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical 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