Gold nanoclusters (GNCs), due to their super high specific surface, have extraordinary high capacity to carry nucleic acids such as siRNA. In recent studies, we focused on targeting nervous environment of tumors because accumulating evidence indicates that the nerves promote tumor development and metastasis. Pancreatic cancer, one of the deadliest human cancers, is closely  related to nervous microenvironment. Pancreatic cancer actively promotes the growth of neurites and stimulate the neurogenesis via the expression of neurotrophic factors such as nerve growth factors (NGFs). Thus, the suppression of NGF expression may inhibit the development of pancreatic cancer. Among various nanomaterials, GNCs had the strongest capacity to conjugate siRNA (226 µmol siRNA per g GNCs). Thus, we used GNCs as nanocarrier to deliver siRNA of NGF (GNC-siRNA) to treat pancreatic cancer. The GNC-siNGF increases the stability of siRNA in serum, prolonges the circulation lifetime of siRNA in blood, and enhances the cellular uptake and tumor accumulation of siRNA. The GNC-siNGF potently down-regulated the NGF expression in Panc-1 cells and in pancreatic tumors, and effectively inhibited the tumor progression in three pancreatic tumor models (subcutaneous model, orthotopic model, and patient-derived xenograft (PDX) model) without adverse effects. Our study demonstrate that knockdown of NGF expression by GNC-siNGF is a promising therapeutic direction for pancreatic cancer.