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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 ( Ir 2 Gd 1 ) that exhibit exceptional mitochondrial targeting capabilities and magneto‐optical bifunctional properties are designed and synthesized. As a single‐molecule theranostic agent, Ir 2 Gd 1 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, Ir 2 Gd 1 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, Ir 2 Gd 1 photocatalytically oxidizes NADH, disrupting the mitochondrial electron transport chain and depleting ATP, further impairing cellular energy metabolism. Mechanistic investigations further reveal that Ir 2 Gd 1 activates the caspase‐3/GSDME signaling axis to induce pyroptosis, a mechanism crucial for overcoming apoptosis resistance and triggering anti‐tumor immune responses. Collectively, Ir 2 Gd 1 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.
Ru et al. (Mon,) studied this question.