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

Abstract

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).