Synergistic nanomedicine overcomes hypoxia-driven DNA repair to potentiate radiotherapy for lung adenocarcinoma.

Abstract

RATIONALE: Radiotherapy (RT) remains a mainstay for inoperable lung adenocarcinoma (LUAD), while its efficacy is frequently compromised by hypoxia-driven radioresistance. Hypoxia stabilizes hypoxia-inducible factor-1α (HIF-1α), which triggers pro-repair DNA damage response (DDR) programs. This process intensifies replication stress and ultimately enhances tumor dependence on ataxia-telangiectasia and Rad3-related (ATR)-dependent checkpoint signaling for survival. Coordinated suppression of these adaptive programs may overcome hypoxia-driven tolerance to RT and improve therapeutic responses. METHODS: The clinical relevance of HIF-1α and ATR signaling in LUAD was established through integrative bioinformatic analyses of a patient cohort. A redox-responsive polymeric nanoplatform incorporating gadolinium (Gd³⁺) and pyropheophorbide a (Ppa) was constructed to enable X-ray-activated radiodynamic therapy (RDT) and co-deliver HIF-1α siRNA with AZD6738, an ATR inhibitor. Therapeutic efficacy, radiosensitization, and mechanisms were studiedand in a LUAD patient-derived xenograft (PDX) model. RESULTS: Bioinformatic analyses support the rationale for simultaneously targeting hypoxia-adaptive programs and checkpoint-mediated DDR. The nanomedicine achieves efficient co-delivery of HIF-1α siRNA and AZD6738, suppressing hypoxia-driven adaptation and impairing ATR-dependent checkpoint protection. In addition, Gd³⁺ promotes X-ray energy deposition to activate Ppa, amplifying radiodynamic reactive oxygen species (ROS) generation. These complementary biological and physicochemical actions synergistically enhance tumor cell killing and markedly improve radiosensitivityand. CONCLUSIONS: This study establishes a synergistic nanotherapeutic strategy to concurrently disrupt the HIF-1α/ATR axis and augment radiodynamic ROS production. By integrating biological pathway inhibition with damage amplification, our strategy effectively overcomes hypoxia-mediated radioresistance, offering a promising and translatable paradigm for enhancing RT outcomes in LUAD.