Biomimetic Nanomedicine Aligns Oxygen‐Sparing Metabolism With Light‐Triggered Therapy for Enhanced Antitumor Efficacy

Tumor hypoxia is prevalent across solid malignancies and limits the effectiveness of oxygen‐dependent therapies. To address this, we report a biomimetic nanomedicine based on M1 macrophage‐derived vesicles co‐loaded with lonidamine (Lon) and the near‐infrared dye IR780 (M1‐Lon‐IR780), which reduces mitochondrial oxygen consumption and thereby enables photodynamic effects under 808‐nm irradiation. Benefiting from the intrinsic tumor‐homing capacity of M1 macrophage‐derived vesicles, M1‐Lon‐IR780 achieves efficient tumor enrichment. Lon reduced mitochondrial respiration and oxygen consumption, thereby increasing oxygen availability during irradiation and enhancing IR780‐mediated reactive oxygen species generation under 808‐nm light. The results show that M1‐Lon‐IR780 strengthens light‐triggered cytotoxicity and induces mitochondrial depolarization and apoptosis compared with monotherapies in vitro. In an A549 xenograft, M1‐Lon‐IR780 with 808 nm irradiation produced stronger tumor growth inhibition than controls without evident systemic toxicity. These findings indicate that integrating metabolic modulation with near infrared photosensitization can mitigate hypoxia‐related limitations, offering a promising strategy for improving photodynamic therapy (PDT).