Metal–organic layer delivers 3-bromopyruvate to mitochondria for metabolic regulation and cancer radio-immunotherapy

Abstract

Abnormal cancer metabolism causes hypoxia and immunosuppression, limiting the anti-tumor efficacy of radiotherapy. Herein, we report a positively charged, mitochondria-targeted nanoscale metal–organic layer conjugated with 3-bromopyruvate (BP), BP/Hf₁₂-Ir, for metabolic reprogramming and radiosensitization. BP/Hf₁₂-Ir disrupts oxidative phosphorylation and glycolysis, reducing energy production and alleviating hypoxia to enhance radiotherapy and anti-tumor immunity. BP/Hf₁₂-Ir in combination with X-ray irradiation inhibits tumor growth by 95% and prevents lung metastasis in mouse models. When further combined with immune checkpoint blockade, this treatment induces robust anti-tumor immunity, achieving 98% tumor growth inhibition.