Co-delivery of cisplatin and Bmi1 siRNA via nanocapsules overcomes chemoresistance in ovarian cancer

Ovarian cancer (OC) is a leading cause of gynecological cancer mortality, primarily due to chemotherapy resistance and tumor recurrence. Cancer stem cells (CSCs), regulated by key factors like Bmi1, play a pivotal role in this resistance by maintaining CSC self-renewal and promoting tumor progression. However, effective treatments targeting these mechanisms remain limited. We engineered a lipid-coated calcium carbonate-based nanocapsule system (CCL) for co-delivery of cisplatin and Bmi1 siRNA (CCL@Bmi1 siRNA) to overcome cisplatin resistance in OC. Bioinformatics analysis revealed significant upregulation of Bmi1 in OC tissues, correlating with poor prognosis. In vitro, CCL@Bmi1 siRNA significantly enhanced cisplatin sensitivity in resistant SK-OV-3/DDP cells. In vivo studies using xenograft and primary ovarian cancer mouse models demonstrated marked tumor growth suppression following treatment with CCL@Bmi1 siRNA, without notable systemic toxicity. Immunohistochemical analyses showed reduced expression of CSC-associated and multidrug resistance markers in tumor tissues. These findings suggest that Bmi1-targeted co-delivery nanotherapeutics represent a promising strategy to counteract chemoresistance and improve therapeutic outcomes in OC.