Biomimetic fusion nanosystem from ginger exosomes and tumor cell membranes: boosting PLK1-targeted therapy in BRCA-heterogeneous HGSOC.

High-grade serous ovarian carcinoma (HGSOC) remains a lethal malignancy with few effective therapeutic options. In this study, we systematically evaluated the anti-tumor effect of Bi2536, an inhibitor of Polo-like kinase 1 (PLK1), in HGSOC, and clarified its mechanism. Bi2536 inactivates PLK1, leading to the subsequent inactivation of cyclin-dependent kinase 1 (CDK1). This disruption triggers a cascade of antitumor effects, including G2/M phase arrest, induction of mitochondrial apoptosis, and suppression of cell migration and invasion. Furthermore, we identified circadian oscillations in PLK1 expression both in HGSOC cells and in vivo xenograft models. To enhance therapeutic precision and minimize systemic toxicity, we engineered a biomimetic nano-delivery system for Bi2536. This integrated platform combines chemotherapy and chemodynamic therapy (CDT), significantly improving antitumor outcomes. Importantly, synchronizing Bi2536 administration with the circadian peaks of PLK1 expression further augmented its therapeutic efficacy. In summary, our work establishes that the combination of Bi2536 with a biomimetic nano-delivery system, together with its chronotherapeutic administration, constitutes a highly promising and multifaceted strategy for the treatment of HGSOC.