A stimuli-responsive polymeric ferroptosis drug delivery system for treatment of liver metastases

Liver metastasis remains a therapeutic challenge in advanced cancers. Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, offers promise for targeting apoptosis-resistant metastatic cells. However, the clinical application of ferroptosis inducers is hindered by poor pharmacokinetics and off-target toxicity. Here, we developed a tumor microenvironment (TME)-responsive polymeric nanomedicine, NP-R-M, to co-deliver the small molecule ferroptosis inducer RSL3, along with a matrix metalloprotease 9 (MMP-9)-cleavable melittin. The nanoparticle leverages MMP-9 expression in metastatic niches to release melittin, enhancing tumor membrane permeability and RSL3 uptake. The formation of protein corona further promotes the targeting of liver metastasis while minimizing systemic toxicity. In vitro, NP-R-M induced ferroptosis with reactive oxygen species (ROS) accumulation, lipid peroxidation, and mitochondrial dysfunction, with specificity dependent on MMP-9 activity. In murine liver metastasis models, NP-R-M demonstrated enhanced tumor accumulation, reduced metastatic burden by 70%, and was associated with prolonged survival. Mechanistically, NP-R-M reversed immunosuppression via depletion of M2 macrophages and recruitment of cytotoxic CD8⁺ T cells. This study addresses limitations for harnessing ferroptosis by integrating enzyme-responsive drug release and immune modulation, offering a strategy against refractory liver metastases.