A novel nanocarrier based on natural polyphenols enhancing gemcitabine sensitization ability for improved pancreatic cancer therapy efficiency.

Pancreatic cancer (PC) is a highly lethal malignancy with rapid progression and poor prognosis. Despite the widespread use of gemcitabine (Gem)-based chemotherapy as the first-line treatment for PC, its efficacy is often compromised by significant drug resistance. 1,2,3,4,6-Pentagaloyl glucose (PGG), a natural polyphenol, has demonstrated potential in sensitizing PC cells to Gem. However, its clinical application is limited by poor water solubility and bioavailability. In this study, we developed a novel PGG-based nanocarrier (FP) using a straightforward, one-step self-assembly method with Pluronic F127 and PGG. Our results showed that FP induced DNA damage and immunogenic cell death (ICD) in both cell experiments and patient-derived organoid models, exhibiting potent anti-tumor effects. Furthermore, in mouse KPC and PDX models, FP, when combined with Gem, showed enhanced Gem sensitization compared to pure PGG, largely due to increased DNA damage and ICD induction. These findings demonstrate the potential of FP to improve the stability and utilization of PGG as effective Gem sensitizers in the treatment of pancreatic cancer, providing a promising pathway for clinical application and translational research.