A novel folate receptor-targeted curcumin nano-delivery system: A dual therapeutic strategy for precise inhibition of MRCKβ to suppress ovarian cancer proliferation and immune escape

Curcumin is a natural polyphenolic compound extracted from the rhizomes of Curcuma longa, exhibiting diverse biological activities, including anti-inflammatory, antioxidant, antitumor, antibacterial, antiviral, and neuroprotective effects. However, its clinical application is severely limited by poor oral absorption and low bioavailability. To address these challenges, this study synthesized a novel folate-targeted curcumin-loaded material—CU-FRα/PEG-2-CHO. This delivery system significantly enhances tumor cell uptake efficiency through folate receptor (FRα)-mediated active targeting (FRα denotes the folate receptor alpha subtype). Additionally, polyethylene glycol (PEG) modification and aldehyde (-CHO) functionalization further improve its water solubility and stability. Experimental results demonstrate that this material not only substantially increases curcumin's absorption rate and bioavailability but also enhances its antitumor activity via targeted delivery mechanisms. This study developed a new type (significantly improving various performances) folate receptor-targeted curcumin nano-delivery system (CU-FRα/PEG-2-CHO) and systematically compared the antitumor effects of two curcumin nanomaterials (CU-FRα/PEG-1-CHO and CU-FRα/PEG-2-CHO), demonstrating that CU-FRα/PEG-2-CHO significantly inhibited the growth of A2780 and HO8910PM ovarian cancer cell lines. After targeting tumor cells, CU-FRα/PEG-2-CHO released curcumin, which was mechanistically shown to specifically target Cdc42-binding kinase β (MRCKβ, IC₅₀ = 2.12 μM), with its binding characteristics confirmed by surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and cellular thermal shift assay (CESTA). Molecular docking analysis revealed that MRCKβ precisely binds to the ATP-binding pocket of curcumin. Further transcriptomic analysis demonstrated that MRCKβ silencing significantly affected the TGF-β-SMAD4-LAG-3 signaling pathway, and CU-FRα/PEG-2-CHO exerted its therapeutic effects by regulating the MRCKβ-APC-SMAD4-CTLA-4 signaling axis to suppress tumor cell proliferation and immune evasion. Animal experiments confirmed that CU-FRα/PEG-2-CHO administration at a dose of 1 mg/kg every two days significantly inhibited tumor growth with a dose-dependent effect. Notably, although cisplatin (5 mg/kg every two days) and αPD-L1 (5 mg/kg every two days) also showed certain therapeutic effects, their tumor suppression efficacy was significantly lower than that of CU-FRα/PEG-2-CHO. These findings not only elucidate the mechanism of a novel folate receptor-targeted curcumin nanoliposome but also provide important evidence for developing MRCKβ-targeted therapeutic strategies against ovarian cancer.