Zhu Lin, Zu Mali, Wu Feifan, Ma Xu, Zhang Shuhui, Zhang Tianchen, Li Xingfan, Yang Huiru, Li Zhenqi, Yu Zetao, Nie Ruijie, Ji Tianjiao, Zhang Xiuping, Liu Rong
The First Clinical Medical School, Lanzhou University, Lanzhou, 730013, China; Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100853, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China; The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China.
Biomaterials. 2026 Feb;325:123599. doi: 10.1016/j.biomaterials.2025.123599. Epub 2025 Aug 6.
Portal vein tumor thrombus (PVTT) is a common and severe indicator in advanced hepatocellular carcinoma (HCC), characterized by a poor prognosis and limited response to existing therapies. Cancer-associated fibroblasts (CAFs) play an important role in promoting HCC metastasis and contribute to resistance against sorafenib (SOR) resistance, which is a standard treatment for advanced HCC. The data from single-cell RNA sequencing highlights the critical role of C-X-C motif chemokine ligand 12 (CXCL12) in the activation of CAFs. To address these challenges, we develop a PVTT-targeted nanocarrier designed to co-deliver small interfering RNA (siRNA) and a multikinase inhibitor, aiming to enhance therapeutic outcomes for PVTT. This novel lipid-coated polylactide-co-glycolide nanoparticle system effectively downregulate CXCL12 expression in CAFs, leading to their inactivation and subsequent reshaping of the tumor microenvironment. The resulting modulation of the tumor microenvironment significantly suppress tumor cell migration, invasion, and resistance to SOR, thereby demonstrating potent anti-tumor effects in orthotopic mouse models of PVTT. Furthermore, RNA sequencing reveals key regulatory pathways and genes associated with the inhibition of SOR resistance and PVTT formation mediated by these nanoparticles. These findings suggest that modulating the tumor microenvironment, combined with targeted anti-tumor therapies, offers a promising strategy for treating HCC patients with PVTT.
门静脉肿瘤血栓（PVTT）是晚期肝细胞癌（HCC）中常见且严重的指标，其预后较差，对现有治疗的反应有限。癌症相关成纤维细胞（CAFs）在促进肝癌转移中起重要作用，并导致对索拉非尼（SOR）产生耐药性，而索拉非尼是晚期肝癌的标准治疗药物。单细胞RNA测序数据突出了C-X-C基序趋化因子配体12（CXCL12）在CAFs激活中的关键作用。为应对这些挑战，我们开发了一种靶向PVTT的纳米载体，旨在共同递送小干扰RNA（siRNA）和多激酶抑制剂，以提高PVTT的治疗效果。这种新型脂质包被的聚乳酸-羟基乙酸共聚物纳米颗粒系统有效地下调了CAFs中CXCL12的表达，导致其失活并随后重塑肿瘤微环境。肿瘤微环境的这种调节显著抑制肿瘤细胞的迁移、侵袭以及对SOR的耐药性，从而在PVTT原位小鼠模型中显示出强大的抗肿瘤作用。此外，RNA测序揭示了与这些纳米颗粒介导的SOR耐药性抑制和PVTT形成相关的关键调控途径和基因。这些发现表明，调节肿瘤微环境并结合靶向抗肿瘤治疗，为治疗PVTT的肝癌患者提供了一种有前景的策略。
