Enzyme-responsive biomimetic ferritin nanoparticles for selective cancer therapy

Plasma membrane rupture offers promising potential for cancer therapy by physically disrupting cell membranes. However, its clinical use is limited by non-selective cytotoxicity, particularly hemolysis, during systemic administration. Here, we propose a biomimetic nanoplatform, designed for precise, enzyme-mediated activation of natural cytolytic peptides (NCPs) within tumor microenvironments. The biomimetic ferritin nanoparticles (MMFn) are engineered constructs comprising NCPs conjugated with an MMP-2/9-responsive peptide and human ferritin (HFn) subunit. The MMFn remain inactive circulation, mitigating nonspecific toxicity, and are selectively reactivated in tumor sites. In MCF-7-TamR cells, MMFn upregulated phosphorylated P38 while downregulating mTOR and PD-L1, indicating effective tumor modulation. In extensive xenograft models, including MC38 colorectal, Panc02 pancreatic, drug-resistant breast cancer, and patient-derived xenografts, MMFn superior tumor targeting and robust antitumor immunity without systemic toxicity. This "deactivation-reactivation" strategy addresses tumor resistance and reprograms immunosuppressive microenvironments, offering a potent therapeutic approach for diverse malignancies.