Aptamer-functionalized exosomes co-delivering miR-934 inhibitor and gemcitabine for targeted pancreatic cancer therapy

Abstract

Pancreatic cancer remains a malignancy with limited treatment efficacy and high resistance to chemotherapy. miR-934 was identified as an oncogenic miRNA significantly upregulated in pancreatic cancer, promoting tumor progression, epithelial-mesenchymal transition (EMT), and chemoresistance by targeting the tumor suppressor PRUNE2. Inhibition of miR-934 sensitized cancer cells to Gemcitabine (GEM)-induced apoptosis, highlighting its therapeutic potential. To enhance delivery efficiency, AS1411 (oligonucleotide aptamer of nucleolin)-functionalized exosomes were engineered to co-deliver miR-934 inhibitor and GEM. The functionalized exosomes demonstrated high encapsulation efficiency, enhanced cellular uptake and tumor-targeting capability, and improved suppression of malignant phenotypes. This platform not only suppressed cell migration, invasion, and EMT but also enhanced GEM-induced apoptosis by restoring PRUNE2 expression and activating pro-apoptotic pathways. Furthermore, PRUNE2 overexpression reversed the malignant phenotypes and gemcitabine resistance induced by miR-934, further confirming the critical role of the miR-934/PRUNE2 axis in pancreatic cancer progression. In vivo, AS1411-functionalized engineered exosomes co-delivering miR-934 inhibitor and gemcitabine exhibited enhanced tumor accumulation and significantly suppressed tumor growth compared with free drug treatment and non-functionalized exosomes. These findings underscore the potential of aptamer-functionalized exosomes as a targeted therapeutic strategy for pancreatic cancer by integrating miRNA modulation and chemotherapeutic delivery.