Biodegradable zwitterionic polymer-cloaked defective metal-organic frameworks for ferroptosis-inducing cancer therapy

Ferroptosis inhibits tumor growth by iron-dependently accumulating lipid peroxides (LPO) to a lethal extent, which can result from iron overload and glutathione peroxidase 4 (GPX4) inactivation. In this study, we developed biodegradable zwitterionic polymer-cloaked atorvastatin (ATV)-loaded ferric metal-organic frameworks (Fe-MOFs) for cancer treatment. Fe-MOFs served as nanoplatforms to co-deliver ferrous ions and ATV to cancer cells; the zwitterionic polymer membrane extended the circulation time of the nanoparticles and increased their accumulation at tumor sites. In cancer cells, the structure of the Fe-MOFs collapsed in the presence of glutathione (GSH), leading to the depletion of GSH and the release of ATV and Fe²⁺. The released ATV decreased mevalonate biosynthesis and GSH, resulting in GPX4 attenuation. A large number of reactive oxygen species were generated by the Fe²⁺-triggered Fenton reaction. This synergistic effect ultimately contributed to a lethal accumulation of LPO, causing cancer cell death. The findings both in vitro and in vivo suggested that this ferroptosis-inducing nanoplatform exhibited enhanced anticancer efficacy and preferable biocompatibility, which could provide a feasible strategy for anticancer therapy.