Estrogen Axis-Targeted Nanocatalytic Synergetic Therapy against Refractory Ovarian Cancer

The malignant progression of estrogen-dependent ovarian cancer is driven by abnormally elevated estrogen levels and the resultant hyperactivation of estrogen receptor alpha (ERα) signaling. Current estrogen-targeting therapies suffer significantly from the inefficient clearance of estrogen and its active metabolites, while functional imbalance between oncogenic ERα and tumor-suppressive estrogen receptor beta (ERβ) contributes to the limited success in conventional endocrine treatments. To this end, this study proposes an integrated “estrogen clearance-ERα/ERβ rebalancing-macrophage reprogramming” therapeutic strategy to treat refractory estrogen axis-driven malignancies. Briefly, a tumor-acidity-responsive copper-genistein nanoreactor has been constructed to achieve the catalytic therapy through the following pathway: First, Cu2+ continuously clears up estradiol via highly efficient catalytic oxidation, directly severing its tumor-promoting signaling source; meanwhile, the generated reactive oxygen species (ROS) from this catalytic process concurrently degrade oncogenic ERα, and the coreleased genistein activates tumor-suppressive ERβ, restoring the functional receptor balance between ERα and ERβ; finally, a comprehensive blockade of pro-tumorigenic signaling and the immunosuppressive tumor microenvironment reversal are achieved through the highly efficient catalytic estrogen clearance and synchronous receptor modulation. This study establishes a paradigm for overcoming therapeutic endocrine resistance in ovarian cancer.