Ferroptosis, an iron-dependent, non-apoptotic form of regulated cell death, has demonstrated promising potential for the treatment of cancers, especially those resistant to common treatments (Dixon et al., 2012, Lei et al., 2022, Peng et al., 2023, Viswanathan et al., 2017, Zhang et al., 2023). Cancer cells exhibit an inherent susceptibility to ferroptosis owing to high levels of reactive oxygen species (ROS), metabolic mutations, and an increased requirement for iron. Ferroptosis occurs when the generation of lipid peroxides (LPO) exceeds the buffering capacity of the antioxidant defense systems, especially the glutathione peroxidase 4 (GPX4)-glutathione (GSH) system (Chen et al., 2021, Lei et al., 2022, Yang et al., 2014b). GPX4 is an important enzyme that utilizes GSH as a co-substrate and reduces toxic LPO to innoxious lipid alcohols, thereby mitigating oxidative damage to cell membranes and detoxifying ferroptosis. Both GPX4 inhibition and GSH depletion cause excessive accumulation of LPO and subsequent cell death (Ingold et al., 2018, Yang et al., 2014b). Several ferroptosis inducers have been identified including statins, erastin, sorafenib, and artemisinin (Chen et al., 2021, Shimada et al., 2016). Among these, statins, prescribed agents for lowering cholesterol, have emerged as promising candidates for inducing ferroptosis (Moosmann and Behl, 2004, Yao et al., 2021). Statins (including atorvastatin (ATV), fluvastatin, and simvastatin) initiate ferroptosis by competitively inhibiting the activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which catalyzes the conversion of HMG-CoA to mevalonate, the rate-limiting enzyme in the mevalonate pathway. This causes a decline in the biosynthesis of selenoproteins including GPX4 (Friedmann Angeli and Conrad, 2018, Viswanathan et al., 2017). For example, a window of opportunity trial in breast cancer revealed that ATV might exert an anti-proliferative effect in cancers overexpressing HMGCR (Bjarnadottir et al., 2013).

As discussed above, the increased requirement for iron to support cancer cell proliferation renders them intrinsically vulnerable to ferroptosis (Jiang et al., 2021, Manz et al., 2016, Torti and Torti, 2013). Excessive iron ions primarily amplify lipid peroxidation by initiating the Fenton reaction (Conrad and Pratt, 2020) and catalyzing metabolic enzymes (Kuhn et al., 2015). In addition, GPX4 attenuation prolongs the longevity of phospholipid hydroperoxides, which can be augmented by the Fenton reaction (Conrad and Pratt, 2020). Thus, it is feasible to optimize and develop iron-based nanoplatforms to co-deliver exogenous iron ions and ferroptosis inducers to cancer cells. Numerous studies have reported that these nanoplatforms can be degraded within cancer cells to release iron ions, thereby intensifying lipid peroxidation (Chen et al., 2020, Hou et al., 2016, Ma et al., 2020, Shen et al., 2018, Wan et al., 2020, Wang et al., 2021, Zhao et al., 2023, Zheng et al., 2021). Yao et al. reported that simvastatin-loaded Fe3O4 nanoparticles coated with zwitterionic polymer membranes effectively killed triple-negative breast cancer (TNBC) (Yao et al., 2021). Hou et al. suggested that ferritin induced ferroptosis by perturbing intracellular iron homeostasis through its autophagic degradation (Hou et al., 2016). Ferric metal–organic frameworks (Fe-MOFs) are hybrid porous coordination polymers with high drug loading and excellent biocompatibility. These frameworks are formed by combining the inorganic ferric nodes with organic ligands (Haddad et al., 2020, Liu et al., 2021, Ma et al., 2020, Shen et al., 2018, Wan et al., 2020, Zhou et al., 2021). Importantly, the properties (e.g., pore size and surface area) and functions of Fe-MOFs can be manipulated by altering their inorganic iron (Fe2+ or Fe3+) subunits and organic linkers (Haddad et al., 2020, Liu et al., 2021, Meng et al., 2021, Zhou et al., 2021).

The physical absorption method is commonly applied for loading drugs into the pores of Fe-MOFs; however, the process is constrained by certain drug properties such as solubility, molecular weight, and drug leakage in the blood (Fu et al., 2021, Haddad et al., 2020, Liu et al., 2021, Meng et al., 2021, Zhou et al., 2021). Therefore, there is a requirement to load drugs as Fe-MOFs defect sites based on defect engineering (Dissegna et al., 2018, Fu et al., 2021). Herein, we constructed biodegradable zwitterionic polymer-cloaked defective metal–organic frameworks for ferroptosis-inducing cancer therapy (Scheme 1). ATV, a ferroptosis inducer, was loaded into Fe-MOFs based on defect engineering (ATV@FM) and a GSH-degradable zwitterionic polymer membrane, poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC), was coated onto the surface of the Fe-MOFs (ATV@FM@PMPC). The PMPC membrane would enhance stability and prolong the blood circulation time of nanoparticles, ultimately increasing their accumulation in tumor sites (Peng et al., 2020). In cancer cells, ATV@FM@PMPC was degraded in the presence of GSH, which reduced disulfide bonds to the sulfhydryl groups in zwitterionic polymers and Fe3+ to Fe2+ in Fe-MOFs, thus releasing ATV and Fe2+ while depleting GSH. Finally, GPX4 expression was declined by ATV and GSH depletion, and the Fenton reaction was triggered by Fe2+, ultimately initiating ferroptosis and suppressing tumor growth.