Impact of the intracellular mechanical microenvironment of breast cancer and normal mammary epithelial cells on magnetic hyperthermia of Fe3O4 nanoparticles.

Magnetic hyperthermia has been widely investigated as a promising cancer treatment modality. Efficient heat generation by magnetic nanoparticles under an alternating magnetic field (AMF) is critical for therapeutic efficacy. While extracellular conditions in the tumor microenvironment are considered key determinants of heat generation, the impact of the intracellular microenvironment has received less attention. This study aimed to elucidate how cytoskeletal architecture and intracellular mechanical properties-key components of the intracellular microenvironment-affect the heat generation and hyperthermia efficiency of magnetic Fe₃O₄ nanoparticles (Fe₃O₄ NPs) in human breast carcinomas and normal human mammary epithelial cells. Under AMF exposure, identical amounts of internalized Fe₃O₄ NPs produced different heating effects in the two cell types, resulting in differential magnetic hyperthermia efficiency. Fe₃O₄ NPs internalized by breast carcinomas produced greater temperature increase and induced apoptosis more effectively than those in normal mammary epithelial cells. Moreover, alternating current susceptibility analysis revealed that the softer intracellular cytoskeletal mechanics of breast carcinomas enhanced magnetothermal conversion compared with that of normal mammary epithelial cells. These findings highlight the critical role of intracellular cytoskeletal mechanics in regulating the magnetothermal behavior of Fe₃O₄ NPs during magnetic hyperthermia. STATEMENT OF SIGNIFICANCE: This study reveals the critical role of the intracellular mechanical microenvironment of breast cancer cells in magnetothermal conversion of magnetic nanoparticles. Breast cancer cells have less organized cytoskeletal structure and softer intracellular microenvironment that are inherently more conducive to the magnetothermal conversion and heating performance of Fe₃O₄ NPs than normal cells. Fe₃O₄ NPs internalized by breast cancer cells generate higher local temperatures and induce significantly greater apoptotic effects. These findings highlight the breast cancer cell intracellular microenvironment as a key determinant in the effectiveness of magnetic hyperthermia, offering new insights into the design and optimization of nanoparticle-based cancer therapies.