Magnetothermodynamic Therapy Enables Selective Elimination of Cancer Cells in Perivascular Hepatocellular Carcinoma

Thermal ablation has emerged as a frontline clinical intervention for treating various malignant tumors, yet its therapeutic efficacy in perivascular hepatocellular carcinoma (HCC) is severely limited owing to the indiscriminate thermal injury to critical vascular structures. In this study, we demonstrate a magnetothermodynamic strategy wherein intracellular magnetic hyperthermia (IMH) thermally enhances tumor-specific chemodynamic reactivity, generating a synergistic cytotoxic effect that selectively kills cancer cells while sparing critical normal tissue. Leveraging ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) as mediators of this strategy, we show that IMH induces a 2.16-fold greater susceptibility in Hepa1-6 cancer cells compared to AML-12 hepatocytes (intracellular IC₅₀: 21.26 vs 45.97 pg Fe/cell), as quantified by a modified selectivity index defined as the IC₅₀ ratio of normal to tumor cells. Mechanistic studies revealed that the localized heating effect of IMH selectively amplifies Fenton reactivity in tumor cells, resulting in a 1.47-fold increase in cytotoxic hydroxyl radicals' generation compared to normal hepatocytes. Correspondingly, therapeutic selectivity was primarily redox-driven, with oxidative stress accounting for 72% of the total effect, as determined using γ-FVIOs controls that generate comparable heat but negligible hydroxyl radicals, while only 28% was attributable to thermal injury alone. In a rabbit VX2 perivascular HCC model, FVIO-mediated magnetothermodynamic therapy achieved an 88.47% tumor inhibition rate within 20 days, while preserving vascular integrity and sparing normal hepatocytes. This magnetothermodynamic paradigm leverages tumor-intrinsic redox vulnerabilities to overcome the anatomical limitations of thermal ablation, establishing a blueprint for precision treatment of vasculature-adjacent malignancies.