Abstract
<p>Due to the heterogeneity of the <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/tumor-microenvironment" title="Learn more about tumor microenvironment from ScienceDirect's AI-generated Topic Pages">tumor microenvironment</a>, the clinical efficacy of tumor treatment is not satisfied, highlighting the necessity for new strategies to tackle this issue. To effectively treat breast tumors by tumor-targeted chemo/chemodynamic therapy, herein, the Fe<sup>3+</sup>-rich MIL-88B nanobullets (MNs) covered with <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/hyaluronic-acid" title="Learn more about hyaluronic acid from ScienceDirect's AI-generated Topic Pages">hyaluronic acid</a> (HA) were fabricated as vehicles of <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/zoledronic-acid" title="Learn more about zoledronic acid from ScienceDirect's AI-generated Topic Pages">zoledronic acid</a> (ZA). The attained ZA@HMNs showed a high ZA payload (ca 29.6 %), outstanding colloidal stability in the serum-containing milieu, and accelerated ZA as well as Fe<sup>3+</sup> release under weakly acidic and <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/glutathione" title="Learn more about glutathione from ScienceDirect's AI-generated Topic Pages">glutathione</a> (GSH)-rich conditions. Also, the ZA@HMNs consumed GSH by GSH-mediated Fe<sup>3+</sup> reduction and converted H<sub>2</sub>O<sub>2</sub> into <img alt="radical dot" src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/55/entities/rad.gif" />OH via Fenton or Fenton-like reaction with pH reduction. After being internalized by 4T1 cells upon CD44-mediated endocytosis, the ZA@HMNs depleted intracellular GSH and degraded H<sub>2</sub>O<sub>2</sub> into <img alt="radical dot" src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/55/entities/rad.gif" />OH, thus eliciting lipid peroxidation and mitochondria damage to suppress cell proliferation. Also, the ZA@HMNs remarkably killed macrophage-like RAW 264.7 cells. Importantly, the in vivo studies and ki67 and <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/phospholipid-hydroperoxide-glutathione-peroxidase" title="Learn more about GPX4 from ScienceDirect's AI-generated Topic Pages">GPX4</a> staining of tumor sections demonstrated that the ZA@HMNs efficiently accumulated in 4T1 tumors to hinder tumor growth via ZA chemotherapy combined with <img alt="radical dot" src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/55/entities/rad.gif" />OH-mediated <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/ferroptosis" title="Learn more about ferroptosis from ScienceDirect's AI-generated Topic Pages">ferroptosis</a>. This work presents a practicable strategy to fabricate ZA@HMNs for breast tumor-targeted chemo/chemodynamic therapy with potential clinical translation.</p>