Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.targeted therapy | gene therapy P ancreatic cancer is an aggressive disease that develops in a relatively symptom-free manner and in most cases, is already advanced at the time of diagnosis (1). It has one of the highest fatality rates of all cancers and is one of the leading causes of cancer-related deaths in the Western world (1, 2). Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic neoplasm, responsible for 95% of pancreatic cancer cases (3). Genetic alterations in the KRAS signaling pathway are involved in over 90% of pancreatic cancer cases (4-6). KRAS mutations were shown to be an early event in the development of pancreatic cancer (5,7,8).The most common KRAS mutation of the human pancreas adenocarcinoma is a gain-of-function substitution mutation of glycine at codon 12 to aspartate (G12D) (5, 9-11). Moreover, PDA cancer cell growth was shown to be dependent on the activity of the mutated KRAS (5, 11) and accordingly, silencing KRAS has proven effective in controlling pancreatic cell line proliferation (12). Here, we aimed to harness the advantages of siRNA technology as a therapeutic modality for pancreatic cancer.Parenteral controlled drug delivery systems are used to improve and advance the therapeutic effects of drug treatments by providing optimized local drug concentrations over prolonged periods of time, reduction of side effects, and cost reduction (13). A prominent method of controlling the release rate of a drug in a pharmaceutical dosage is to embed the active ag...