The normal chemotherapy only induces the intracellular apoptosis pathway to promote primary tumor cells death, while not inhibit tumor metastasis. Herein, we proposed a kind of heparanase (HPSE)-driven sequential released nanoparticles, which modified with β-cyclodextrin (β-CD) grafted heparin (NLC/H(D + F + S) NPs) co-loading with doxorubicin (DOX), ferrocene (Fc), and TGF-β receptor inhibitor (SB431542). NLC/H(D + F + S) NPs successfully inhibited breast cancer metastasis by intracellular and extracellular hybrid mechanism. DOX and Fc loaded in NLC/H(D + F + S) NPs effectively enhanced intracellular ROS level to activate ferroptosis pathway, the enhanced ROS also induced the apoptosis pathway and decreased MMP-9 expression to synergize with ferroptosis for tumor therapy. In extracellular site, SB431542 was sequentially released by HPSE-driven, which blocked tumor metastasis by modulating tumor microenvironment, decreasing TAFs activation, and reducing the secretion of TGF-β. In addition, anti-tumor immune response induced by ferroptosis further strengthened the effect of tumor therapy. Finally, under the help of intracellular and extracellular mechanisms launched by NLC/H(D + F + S) NPs, the satisfactory anti-tumor metastasis effect was obtained in the in vivo anti-tumor assays. Therefore, NLC/H(D + F + S) NPs was a novel dosage regimen for breast cancer therapy through intracellular and extracellular mechanisms, in which ferroptosis induced by ROS played an important role.

正常化学疗法仅诱导细胞内凋亡途径以促进原发性肿瘤细胞死亡，而不抑制肿瘤转移。在本文中，我们提出了一种由乙酰肝素酶（HPSE）驱动的顺序释放纳米颗粒，该纳米颗粒用与阿霉素（DOX）共负载的β-环糊精（β-CD）接枝肝素（NLC / H（D + F + S）NPs）修饰），二茂铁（Fc）和TGF-β受体抑制剂（SB431542）。NLC / H（D + F + S）NPs通过细胞内和细胞外杂交机制成功抑制了乳腺癌的转移。装载在NLC / H（D + F + S）NPs中的DOX和Fc有效地增强了细胞内ROS的水平以激活肥大化途径，增强的ROS还诱导了细胞凋亡途径并降低了MMP-9的表达以与肥大症协同治疗肿瘤。在细胞外部位，SB431542由HPSE驱动的顺序释放，通过调节肿瘤微环境，减少TAFs活化并减少TGF-β的分泌来阻止肿瘤转移。此外，由肥大症引起的抗肿瘤免疫反应进一步增强了肿瘤治疗的效果。最后，在NLC / H（D + F + S）NPs启动的细胞内和细胞外机制的帮助下，获得了令人满意的抗肿瘤转移效果。体内抗肿瘤试验。因此，NLC / H（D + F + S）NPs是一种通过细胞内和细胞外机制治疗乳腺癌的新型给药方案，其中ROS引起的肥大症起着重要的作用。