Magnet-Responsive Nanomaterials Trigger Ferroptosis and Cellular Senescence Modulation via p53/SLC7A11 Axis for Tumor Therapy.

Abstract

Cellular senescence, a state of permanent cell cycle arrest, has emerged as a promising therapeutic avenue. However, conventional pro-senescence agents are limited by poor selectivity, unintended activation of apoptosis, and acquired resistance. To address these challenges, we developed a novel nanotherapeutic platform (FAB) that integrated γ-Fe₂O₃ nanoparticles with the MDM2-p53 inhibitor APG-115, sensitizing tumor to therapy via targeting p53/SLC7A11 axis to bidirectionally regulate ferroptosis and induce cell senescence. Under the alternating magnetic field (AMF) exposure, γ-Fe₂O₃ nanoparticles served as biocompatible ferroptosis inducers that generated abundant lipid peroxides (LPO) while simultaneously triggering DNA damage-mediated p53 activation. Concurrently, APG-115 inhibited MDM2-p53 interaction, further stabilizing and amplifying p53 signaling. Mechanistically, elevated p53 transcriptionally repressed SLC7A11, a key subunit of the cystine/glutamate antiporter, resulting in glutathione depletion and GPX4 inactivation. This cascade markedly enhanced ferroptosis, establishing a self-amplifying feedback loop that exacerbated DNA damage and drives irreversible senescence. Notably, senescent tumor cells exhibit increased thermal susceptibility under AMF, ultimately leading to selective apoptosis. Our study not only elucidated the crosstalk between p53 activation and ferroptosis facilitation in mediating senescence but also provided a promising strategy for enhanced tumor treatment.