Enzyme-responsive biomimetic ferritin nanoparticles for selective cancer therapy.

Abstract

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.