Sunitinib lipid nanoparticles remodel tumor vasculature to synergize with two-stage radiotherapy for enhanced radiosensitivity in breast Cancer.

Radiotherapy (RT) is a standard treatment for breast cancer, the most common malignancy in women. However, its efficacy is limited in 20-30 % of patients due to acquired resistance, primarily caused by tumor hypoxia resulting from abnormal vasculature in the tumor microenvironment (TME). Vascular normalization strategies aim to stabilize tumor vasculature and alleviate hypoxia. Although preclinical studies indicate survival benefits from vascular normalization，their clinical translation remains limited by spatiotemporal constraints and a narrow therapeutic window where excessive modulation can induce detrimental effects. Here, we engineered microenvironment-responsive PEGylated lipid nanoparticles (PL) that encapsulate varying doses of sunitinib (Sun@PL) to achieve sustained release, selecting the optimal dose for dose-controlled vascular normalization within tumor tissue. When synergized with "two-stage RT", this strategy effectively enhanced tumor oxygenation and radiosensitization. Initial RT softened the extracellular matrix (ECM), alleviated vascular compression, and amplified Sun@PL-driven normalization, significantly improving tumor oxygenation. The subsequent RT, conducted in the improved oxygenated microenvironment, effectively enhanced anti-tumor efficacy. Our findings emphasize the critical role of dosage and controlled-release strategies in vascular normalization and highlight the potential of synergizing Sun@PL with RT as a strategy to overcome radioresistance in breast cancer and enhance therapeutic efficacy.