pH-responsive 2D niobium carbide nanosheets for targeted circPUM1 siRNA delivery in ovarian cancer therapy

Ovarian cancer progression is closely associated with tumor microenvironment (TME) dysregulation, particularly pathological angiogenesis driven by exosome-mediated crosstalk. Here, we elucidate that ovarian cancer-derived circPUM1 promotes angiogenesis by transferring to vascular endothelial cells via exosomes. Mechanistically, circPUM1 upregulates the expression of RAB27B and VEGFA by sponging miR-607, thus boosting release of exosome facilitated by RAB27B and directly activating VEGF signaling in endothelial cells to foster angiogenesis. To disrupt this circPUM1-driven TME modulation, we engineered an innovative pH-responsive 2D niobium carbide nanosheets loaded with circPUM1 siRNA. Through excessive PEI grafting, we functionalized the nanosheets with cationic property, achieving efficient negative-charged siRNA loading. Further surface PEGylation shielded the nanosheets' positive charge, reducing off-target effect and systemic toxicity, while acidic TME triggered PEG exfoliation for tumor-specific circPUM1 siRNA delivery. Functional cellular assays and an intraperitoneal tumor-bearing mouse model validated that the nanosheet-delivered circPUM1 siRNA effectively inhibited angiogenesis and peritoneal dissemination by knocking down circPUM1 expression and subsequently downregulating its downstream targets. This study uncovers a novel exosome-mediated angiogenesis mechanism and develops innovative MXene nanosheets for pH-responsive siRNA delivery providing a promising strategy for ovarian cancer precision therapy with significant clinical translational value and application potential.