Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Biomimetic nanoparticles (NPs) coated with cell membranes show enhanced biocompatibility and specificity for homotypic cells, and have gained considerable attention for targeted anti-tumor therapy. We constructed cancer cell-macrophage hybrid membrane-coated near infrared (NIR)-responsive hollow copper sulfide nanoparticles encapsulating sorafenib and surface modified with anti-VEGFR (CuS-SF@CMV NPs). These CuS-SF@CMV NPs expressed the characteristic membrane proteins of both cancer cells and macrophages, and selectively accumulated in cancer cells in vitro and tumors in vivo, compared to the CuS NPs. In addition, the CuS-SF@CMV NPs achieved synergistic photo-thermal and chemotherapy in cancer cells upon NIR irradiation, with 94.3% inhibition of tumor growth in a murine hepatoma model. While the initial increase in temperature rapidly killed the tumor cells, sorafenib and the anti-VEGFR antibody sustained the tumor killing effect by respectively inhibiting tumor cell proliferation and angiogenesis via the Ras/Raf/MEK/ERK and PI3K/AKT pathways. Taken together, the CuS-SF@CMV NPs have immune evasion, tumor cell targeting and drug loading capacities, along with an inherent photo-thermal conversion ability, making them ideal for synergistic photo-thermal/chemo therapy against HCC.

Statement of Significance

We created cancer cell-macrophage hybrid membrane-coated hollow CuS NPs encapsulating sorafenib and surface modified with anti-VEGFR antibodies (CuS-SF@CMV). These CuS-SF@CMV NPs enhanced synergistic PTT and chemotherapy against hepatoma cells through homotypic cell targeting, immune escape and inhibition of a tumorigenic signaling pathway. A long-term inhibition of tumor growth and metastasis was achieved owing to the rapid destruction of the cancer cells through photo-thermal conversion by the CuS NPs, and sustained clearance of the tumor cells by sorafenib and anti-VEGFR antibodies.

Our findings suggest that CuS-SF@CMV NPs present great treating effects in preclinical models of HCC, providing the framework for further study in clinical trials to improve patient outcome in hepatocellular carcinoma.

中文翻译：

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杂化膜伪装的硫化铜纳米颗粒用于肝细胞癌的光热化学疗法。

肝细胞癌（HCC）是全球癌症相关死亡的第三大主要原因。涂有细胞膜的仿生纳米颗粒（NPs）对同型细胞显示出增强的生物相容性和特异性，并已成为靶向抗肿瘤治疗的关注重点。我们构建了包被索拉非尼并用抗VEGFR（CuS-SF @ CMV NPs）表面修饰的癌细胞-巨噬细胞杂交膜包被的近红外（NIR）响应的空心硫化铜纳米颗粒。与CuS NPs相比，这些CuS-SF @ CMV NPs表达癌细胞和巨噬细胞的特征性膜蛋白，并且在体外和体内肿瘤中选择性地积累在癌细胞中。此外，在近红外照射下，CuS-SF @ CMV NP在癌细胞中实现了协同的光热和化学疗法，达到94。在鼠肝癌模型中抑制3％的肿瘤生长。当最初的温度升高迅速杀死肿瘤细胞时，索拉非尼和抗VEGFR抗体通过分别通过Ras / Raf / MEK / ERK和PI3K / AKT途径抑制肿瘤细胞的增殖和血管生成而维持了肿瘤的杀伤作用。总之，CuS-SF @ CMV NP具有免疫逃逸，肿瘤细胞靶向和载药能力，以及固有的光热转化能力，使其成为针对HCC的协同光热/化学疗法的理想选择。

重要声明

我们创建了包裹索拉非尼并用抗VEGFR抗体（CuS-SF @ CMV）进行表面修饰的癌细胞-巨噬细胞杂交膜包裹的空​​心CuS NP。这些CuS-SF @ CMV NP通过同型细胞靶向，免疫逃逸和抑制致瘤信号通路增强了针对肝癌细胞的协同PTT和化学疗法。由于通过CuS NPs通过光热转化迅速破坏癌细胞，并通过索拉非尼和抗VEGFR抗体持续清除肿瘤细胞，实现了对肿瘤生长和转移的长期抑制。

我们的发现表明，CuS-SF @ CMV NP在肝癌的临床前模型中显示出巨大的治疗效果，从而为临床试验中进一步研究以改善肝癌患者预后提供了框架。