Harnessing bimetallic iMWA nanosensitizer to unleash ferroptosis and calcium overload: Unlocking tumor vulnerability for potentiated iMWA therapy against hepatocellular carcinoma

Microwave ablation (MWA) holds promise as a tumor treatment modality, yet incomplete ablation with low-frequency MWA (iMWA) remains a significant obstacle to survival, while the high-frequency MWA poses safety concerns. To address these challenges, we introduce a novel bimetallic iMWA nanosensitizer, CFT-NPs, constructed via metal-coordination interactions between tannic acid (TA) and iron/calcium dual metal ions (Fe3+/Ca2+). The Fe3+/Ca2+ in CFT-NPs work in harmony to convert electromagnetic energy into heat, thereby bolstering the effectiveness of iMWA while maintaining good biosafety. Furthermore, the pH-triggered rupture of CFT-NPs release TA, Fe3+, and Ca2+. The liberated Fe3+ undergoes reduction by TA, and when combined with Ca2+, they trigger ferroptosis and Ca2+ overload respectively, significantly amplifying the therapeutic effects of iMWA. Utilization iMWA with CFT-NPs results in lipid oxidation, mitochondrial dysfunction, and disruption of redox balance, both in vitro and in vivo. Notably, this nanosensitizer exerts a robust antitumor effect, effectively inhibiting tumor growth and downregulating the expression of matrix metalloproteinases, which is associated with tumor metastasis. Collectively, this innovative study offers a promising approach to overcome the challenges of incomplete ablation and biological safety, enhancing the antitumor efficacy of iMWA.