The serious drawbacks of conventional pancreatic ductal adenocarcinoma (PDAC) therapy like nonspecific toxicity and high resistance to chemo and radiation therapy, prompted the development and application of countless siRNA-based therapeutics. Significant technological success has been achieved in this area; however, the major challenges to siRNA-based therapeutics becoming a new paradigm in the pancreatic cancer therapy stem from enzymatic digestion, off-target effects, difficulty to enter cells, induction of innate immune responses, and renal clearance. Recent advances in drug delivery systems hold great promise for improving siRNA-based therapeutics and developing a new class of drugs, nano-siRNA drugs. However, a number of fundamental questions, regarding toxicity, immunostimulation, and poor knowledge of nano-bio interactions, need to be addressed before clinical translation. In this review, we provide recent achievements in designing and development of various non-viral delivery vehicles for pancreatic cancer therapy. More importantly, co-delivery of conventional anticancer drugs with siRNA as a new revolutionary pancreatic cancer combinational therapy is completely discussed.