Hyaluronic acid-covered ferric ion-rich nanobullets with high zoledronic acid payload for breast tumor-targeted chemo/chemodynamic therapy

Due to the heterogeneity of the tumor microenvironment, 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 Fe3+-rich MIL-88B nanobullets (MNs) covered with hyaluronic acid (HA) were fabricated as vehicles of zoledronic acid (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 Fe3+ release under weakly acidic and glutathione (GSH)-rich conditions. Also, the ZA@HMNs consumed GSH by GSH-mediated Fe3+ reduction and converted H2O2 into [rad]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 H2O2 into [rad]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 GPX4 staining of tumor sections demonstrated that the ZA@HMNs efficiently accumulated in 4T1 tumors to hinder tumor growth via ZA chemotherapy combined with [rad]OH-mediated ferroptosis. This work presents a practicable strategy to fabricate ZA@HMNs for breast tumor-targeted chemo/chemodynamic therapy with potential clinical translation.