Tehran University of Medical Sciences Acta Medica Iranica 0044-6025 57 2 2019 03 12 83 93 EN Fateme Karimi Dermani Department of Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran. Farid Azizi Jalilian Department of Medical Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran. Hossein Hossienkhani Innovation Center for Advanced Technology, Matrix, Inc., New York, NY 10029, USA. Razieh Ezati Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran. Razieh Amini Department of Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran. AND Molecular Medicine Research Center, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran. 2018 03 26 2018 12 16 Small interfering RNAs (siRNA) technology has shown great promise as a new class of therapeutic interventions for the treatment of cancer and other diseases. It is a remarkable endogenous pathway that can regulate sequence-specific gene silencing. Despite the excitement about possible applications of this biological process for sequence-specific gene regulation, the major limitations against the use of siRNA-based therapeutics are their rapid degradation by serum nuclease, poor cellular uptake, and rapid renal clearance following systemic delivery, off-target effects and the induction of immune responses. Many researchers have tried to overcome these limitations by developing nuclease-resistant chemically-modified siRNAs and a variety of synthetic and natural biodegradable lipids and polymers to enhance the efficacy and safety profiles of siRNA delivery. Ideal siRNA-based delivery systems for cancer therapy must be clinically suitable, safe and effective. In this review, we introduce the greatest challenges in achieving efficient RNAi delivery and discuss design criteria and various delivery strategies for cancer therapy, including chemical modifications, lipid-based nano-vectors, polymer-mediated delivery systems, conjugate delivery systems, and others. https://acta.tums.ac.ir/index.php/acta/article/view/7146 https://acta.tums.ac.ir/index.php/acta/article/download/7146/5216