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

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 studied in vitro and 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 radiosensitivity in vitro and in vivo.

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.