The critical problems of conventional prostate cancer therapeutic strategies like nonspecific toxicity and multi-drug resistance prompted the development and application of countless nanoparticle- based siRNA therapeutics. Unfortunately, siRNA-based therapeutics suffer from the lack of safe and effective delivery systems, immune system stimulation, poor knowledge of nano-bio interactions, and limitations concerning designing, manufacturing, clinical translation, and commercialization. In this review, we provide cutting-edge advances in nanoparticle-mediated siRNA delivery carriers like polymeric systems, lipid systems, specific systems, and rigid nanoparticles for the treatment of prostate cancer. Moreover, co-delivery of conventional chemotherapy drugs with siRNA as a revolutionary robust strategy for prostate cancer combinational therapy is completely covered.