A Multifunctional Nanodrug Increases the Therapeutic Sensitivity of Lenvatinib to Hepatocellular Carcinoma by Inhibiting the Stemness of Hepatic Cancer Stem Cells

Abstract Drug resistance resulting from diverse mechanisms including the presence of cancer stem cells (CSCs) is the main obstacle for improving therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). Herein, a nanomedicine (siCD24‐Len‐MnO@PLAP) is developed by incorporating manganese oxide (MnO), lenvatinib (Len), and siRNA against CD24 (siCD24) into micelles composed of methoxypolyethylene glycol ( m PEG), poly‐L‐lysine (PLLys), and polyasparagyl(N‐(2‐Aminoethyl)piperidine) (PAsp(PIP)) triblock copolymer. The nanomedicine can respond to the tumor microenvironment (TME) to release lenvatinib, and produce Mn 2+ and O 2 , accompanied by changes in nanoparticle charge, which facilitates cellular endocytosis of siCD24‐loaded 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‐derived CSCs and Hepa1‐6‐derived CSCs, the nanomedicine shows remarkable anti‐cancer 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‐1α (HIF‐1α). Moreover, in situ production of paramagnetic Mn 2+ 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‐visible siCD24‐ and lenvatinib‐loaded nanodrug holds great potential in enhancing therapeutic sensitivity for HCC lenvatinib therapy.