ABSTRACT: Glioblastoma (GBM) remains a formidable clinical challenge, characterized by invasive growth, therapeutic resistance and dismal patient survival. We report the development of HITMAN (Highly-localized-electric-field Induced Tumor-therapy using Magnetically Actuated Nanoantennas), a wireless bioelectric therapy that selectively eradicates GBM cells with cellular precision. Magnetically actuated nanoantennas convert low-frequency (≤200 kHz), deep-brain penetrant magnetic fields into localized electric fields (>2 kV m⁻¹), triggering protein unfolding, membrane disruption, and ER stress. In vitro, HITMAN demonstrated superior efficacy compared to temozolomide (TMZ), significantly decreasing viability in drug-resistant, patient-derived GBM cells by 52.2%, versus 10% with TMZ, while sparing neurons and astrocytes. Mechanistically, HITMAN activated unfolded protein response and autophagy pathways, suppressed cell cycle and adhesion genes, reduced Ki-67 expression, disrupted cytoskeletal architecture, and elevated p53 levels, underscoring a multifaceted antitumor mechanism. In orthotopic mouse models, HITMAN significantly inhibited tumor growth, extended median survival by over 50%, and showed no systemic toxicity. Thus, HITMAN offers a minimally invasive, potent, and clinically translatable therapy for GBM.
