Nano-enabled repurposing of Benproperine phosphate enhances pancreatic Cancer chemotherapy through lethal autophagy arrest and immune activation.

Gemcitabine-based chemotherapy remains a cornerstone in pancreatic cancer treatment, yet its efficacy is hindered by poor bioavailability and adaptive resistance mechanisms, such as autophagy. In this study, we developed a hyaluronic acid (HA) modified zeolitic imidazolate framework-8 (ZIF-8) drug-repurposing nanoplatform (HA/ZIF-8@BPP/Gem) against pancreatic cancer through the co-delivery of the antitussive benproperine phosphate (BPP) and gemcitabine (Gem). Using cell lines, patient-derived xenograft models, and orthotopic tumor models, we demonstrated that BPP and Gem, rapidly released from the nanoplatform in the acidic tumor microenvironment, exhibited synergistic cytotoxicity without causing significant biochemical abnormalities or organ toxicity. Mechanistically, BPP initiated autophagy but blocked RAB11A-dependent autophagosome-lysosome fusion, thereby converting Gem-induced protective autophagy into a lethal process. In addition, RNA sequencing and flow cytometry analyses revealed that HA/ZIF-8@BPP/Gem stimulated the secretion of immune-related cytokines and activated immune response pathways, particularly T cell-mediated immunity. In conclusion, our study presents a safe and effective strategy of nano-enabled drug repurposing to improve chemotherapy outcomes by inducing amplified autophagy arrest and immune activation in pancreatic cancer.