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Herein, a nanomedicine (siCD24\u2010Len\u2010MnO@PLAP) is developed by incorporating manganese oxide (MnO), lenvatinib (Len), and siRNA against CD24 (siCD24) into micelles composed of methoxypolyethylene glycol (\n                    <jats:italic>m<\/jats:italic>\n                    PEG), poly\u2010L\u2010lysine (PLLys), and polyasparagyl(N\u2010(2\u2010Aminoethyl)piperidine) (PAsp(PIP)) triblock copolymer. The nanomedicine can respond to the tumor microenvironment (TME) to release lenvatinib, and produce Mn\n                    <jats:sup>2+<\/jats:sup>\n                    and O\n                    <jats:sub>2<\/jats:sub>\n                    , accompanied by changes in nanoparticle charge, which facilitates cellular endocytosis of siCD24\u2010loaded nanoparticles. The released siCD24 and lenvatinib synergistically reduces CD24 expression, resulting in a more pronounced inhibition of stemness of CSCs. In the mouse models of HCC using Huh7\u2010derived CSCs and Hepa1\u20106\u2010derived CSCs, the nanomedicine shows remarkable anti\u2010cancer effect by enhancing the therapeutic effects of lenvatinib against HCC via reducing the expression level of CD24 and decreasing the expression of hypoxia inducible factor\u20101\u03b1 (HIF\u20101\u03b1). Moreover, in situ production of paramagnetic Mn\n                    <jats:sup>2+<\/jats:sup>\n                    from the nanomedicine serves as an excellent contrast agent for magnetic resonance imaging (MRI) to monitor the therapeutic process. This study demonstrates that this multifunctional MRI\u2010visible siCD24\u2010 and lenvatinib\u2010loaded nanodrug holds great potential in enhancing therapeutic sensitivity for HCC lenvatinib therapy.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202401398","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T02:10:27Z","timestamp":1727921427000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Multifunctional Nanodrug Increases the Therapeutic Sensitivity of Lenvatinib to Hepatocellular Carcinoma by Inhibiting the Stemness of Hepatic Cancer Stem Cells"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4003-8455","authenticated-orcid":false,"given":"Xieqing","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Radiology Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical 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