Heparanase-driven sequential released nanoparticles for ferroptosis and tumor microenvironment modulations synergism in breast cancer therapy.

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.