Intersection of ferroptosis and nanomaterials brings benefits to breast cancer

Abstract

Breast cancer (BC) is the most frequently diagnosed malignancy among women worldwide, with a high incidence and mortality rate. Despite advances in treatment, approximately 10%-15% of patients with BC still face recurrence. Therefore, improving BC therapy remains a significant challenge. In this article, we provide a detailed overview, categorizing and elaborating the developments of current research progress on nanodrug delivery systems based on ferroptosis for BC treatment. By increasing the iron content in BC cells and inhibiting the defense system against ferroptosis, the accumulation of lipid peroxides is promoted, and ferroptosis is induced in BC cells. In addition to directly targeting tumor cells, nanodrug delivery systems can remodel the tumor microenvironment, inhibit BC primary growth, and prevent distant metastasis. These nanomaterials, after drug loading and modification, possess characteristics such as smart activation, controlled release, specific targeting, good biocompatibility, and long circulation time, thereby enhancing the efficacy of BC treatment. We also classify and discuss the mechanisms and advantages of different types of nanomaterials. Finally, we discuss how multifunctional nanosystems can sensitize ferroptosis when combined with radiotherapy, chemotherapy, immunotherapy, and phototherapy to achieve synergistic effects in BC treatment. This work reveals the potential of ferroptosis-based nanomaterials in overcoming BC, analyzes the limitations of the clinical application and proposes possible solutions, offering a promising direction for future treatment strategies.

Keywords: Breast Cancer; Ferroptosis; Molecular Mechanisms; Nanomaterials; Treatment.

Fig. 1

Ferroptosis mechanism. Fe³⁺ enters cells via transferrin, is reduced to Fe²⁺ by STEAP3, and catalyzes the Fenton reaction with H₂O₂ to generate •OH. PUFA is enzymatically converted to PUFA-PL, which is prone to lipid peroxidation by •OH, forming toxic PUFA-PL-OOH and inducing ferroptosis. Cystine is imported through System Xc^- and converted into cysteine for GSH synthesis. GSH is essential for GPX4 activity, which inhibits lipid peroxidation and ferroptosis. FSP1 (at the plasma membrane) and DHODH (in mitochondria) reduce CoQ10 to CoQ10H2, suppressing ferroptosis independently of GPX4.

Fig. 2

Iron metabolism regulation in ferroptosis-based nanodrug delivery systems. FeOOH/siPROM2@HA delivers Fe³⁺ and siPROMININ2, which inhibits iron efflux (Fang et al. 2023a). Copyright© 2023 ELSEVIER. FPBC@SN releases ferritin and SRF, suppresses GSH synthesis, and promotes NCOA4-mediated ferritinophagy to elevate intracellular iron levels (Gao et al. 2021). Copyright© 2021 WILEY. UFCL uses UCNPs to convert Fe³⁺ to Fe²⁺ under laser irradiation and releases cisplatin, which activates NOX to generate H₂O₂ and enhance the Fenton reaction (Gell 2018). Copyright© 2022 American Chemical Society. HMCMR delivers Mn²⁺, catalyzing Fenton-like reactions and inhibiting GSH through PTT (Ghadi et al. 2023). Copyright© 2019 American Chemical Society.

Fig. 3

GPX4- mediated ferroptosis defense pathway. The DS in 5-Fu⊂nano DSPP-COF is responsive to GSH, releasing 5-FU that inhibits GPX4 (Herrera-Abreu et al. 2016). Copyright© 2023 Royal Society of Chemistry. SIM released from Fe₃O₄@PCBMA-SIM downregulates HMGCR, affects the MVA pathway, and inhibits GPX4 expression (Hong et al. 2021). Copyright© 2021 Journal of Nanobiotechnology. Cu2-xSe/ZIF-8@Era-PEG-FA depletes GSH via Cu²⁺ and erastin; erastin also upregulates NOX4, increases H₂O₂, and generates O₂ through Cu⁺ oxidation, overcoming HIF-1α–mediated ferroptosis resistance (Hosseinaee et al. 2020). Copyright© 2023 American Chemical Society. The SS in RSL3@CPT-SS-Fc-RGD features GSH-responsive SS bonds, releasing RSL3 to inhibit GPX4 and Fc to activate the Fenton reaction (Chittineedi et al. 2023). Copyright© 2023 ELSEVIER.

Fig. 4

GPX4-dependent LPO pathways in ferroptosis. Aur/PE-AA@MFc releases Fc to increase iron levels, Aur to deplete GSH, and PE-AA to enhance LPO (Isshiki et al. 2001). Copyright© 2023 American Chemical Society. CSO-BHQ-IR780-Hex/MIONPs/Sor releases IR780-Hex, which targets mitochondria and generates ROS to amplify LPO. It also delivers MIONPs to increase iron levels and sorafenib to inhibit system Xc^- (Jarosz-Biej, et al. 2019). Copyright© 2019 American Chemical Society.

Fig. 5

GPX4-independent LPO pathways and p53-related ferroptosis mechanisms. Au NPs released by Au/Cu-TCPP(Fe)@RSL3-PEG-iRGD not only deplete glucose, impair mitochondrial function, inhibit FSP1, but also suppress PPP, reduce NADPH, and limit cysteine synthesis. It also releases RSL3 and Cu ions to inhibit GSH synthesis (Chen et al. 2023c). Copyright© 2021 American Chemical Society. Cu-SF(RSV) NPs release RSV to inhibit FSP1 and CoQH2 synthesis. It also releases SF to inhibit GSH and Cu²⁺ to catalyze Fenton-like reaction (Gong 2024). Copyright© 2022 WILEY. siR/IONs@LDH delivers IONs and siR to inhibit DHODH, disrupting mitochondrial redox homeostasis (Jiang et al. 2023). Copyright© 2022 American Chemical Society. DNAzyme-Fe-HA releases Fe²⁺ and FBXW7 DNAzymes, which degrade FBXW7 mRNA to block the ubiquitination and degradation of p53. Stabilized p53 downregulates SLC7A11. Upon radiation, DNAzyme-Fe-HA also generates ROS (Kim et al. 2015). Copyright© 2023 ELSEVIER.

Fig. 6

Application of different nanocarriers in ferroptosis-based BC treatment. Nanodelivery systems are conducted by utilizing the advantages of different nanocarriers, loading ferroptosis inducers and other substances, and continuously optimizing the nanodrugs, including intelligent release and modified envelope.

Fig. 7

Combination therapy strategies involving ferroptosis-based nanodrugs in BC. Designed nanodrugs not only induce ferroptosis but also synergize with chemotherapy, radiotherapy, immunotherapy, PDT, PTT, SDT, CDT, starvation therapy, and gas therapy. These treatments mutually enhance therapeutic efficacy through complementary mechanisms.

Fig. 8

Mechanism of ferroptosis-based nanodrugs in BC and combination therapy