Magnetically Actuated Iron Oxide Nanoparticles Sensitize Acute T-Lymphocyte Leukemia Cells to Vincristine via Reprogramming Cellular Homeostasis.

Abstract

Vincristine (VCR) is a first-line chemotherapeutic agent for pediatric T-cell acute lymphoblastic leukemia (T-ALL), while its clinical efficacy is limited by dose-dependent peripheral neurotoxicity. As T cells in normal physiological environments experience various mechanical forces and VCR targets a mechanosensitive cellular microtubule, in this study, we developed a magnetically actuated mechanical stimulation (MAMS) strategy utilizing superparamagnetic Fe₃O₄ nanoparticles (IONPs) and an external static magnetic field (MF), which combined with VCR to significantly enhance the chemosensitivity of T-ALL cells. It was demonstrated that the IONPs primarily bound to the membrane of Jurkat cells and formed ordered assembly structures under MF, which disrupted cellular homeostasis by activating the calcium-NFAT-FasL signaling pathway, hyperpolarizing mitochondria, reprogramming metabolism, and disrupting cytoskeletal assembly. In conclusion, the MAMS strategy sensitized Jurkat cells to VCR by multilevel interference with the homeostasis of cells, providing a promising approach for developing more effective and less cytotoxic T-ALL treatment regimens.