A Heterotrinuclear Ir(III)-Gd(III) Complex as a Mito-Bomb for Bimodal Imaging-Guided Precision Cancer Therapy.

Abstract

Multimodal imaging-guided precision therapy has emerged as a cutting-edge theranostic strategy that integrates real-time diagnostic feedback with precision therapeutic intervention in a single platform, significantly enhancing treatment efficacy and minimizing off-target effects. Herein, Ir(III)-Gd(III) heterometallic complexes (Ir²Gd¹) that exhibit exceptional mitochondrial targeting capabilities and magneto-optical bifunctional properties are designed and synthesized. As a single-molecule theranostic agent, Ir²Gd¹ serves as a magnetic resonance imaging (MRI) contrast agent with high relaxivity (9.42 mM^-1 s^-1), while its intrinsic phosphorescence facilitates both optical imaging and phototherapy. Notably, Ir²Gd¹ can selectively accumulate within cancer cell mitochondria. Upon light irradiation, it generates singlet oxygen, which disrupts mitochondrial integrity by inducing cytochrome c release, thereby activating apoptosis or pyroptosis pathways. Additionally, Ir²Gd¹ photocatalytically oxidizes NADH, disrupting the mitochondrial electron transport chain and depleting ATP, further impairing cellular energy metabolism. Mechanistic investigations further reveal that Ir²Gd¹ activates the caspase-3/GSDME signaling axis to induce pyroptosis, a mechanism crucial for overcoming apoptosis resistance and triggering anti-tumor immune responses. Collectively, Ir²Gd¹ functions as a "Mito-Bomb" that targets cancer cells' central powerhouse, executing focused detonation to achieve potent antitumor efficacy. This study presents a novel single-molecule theranostic tool for tumor phototherapy and pyroptosis guided by magneto-optical dual-modal imaging.