The use of Small interfering RNAs (siRNA) is prevalent in various cancer-based therapies. siRNA is a powerful RNAi, which can be used in clinical oncology with nanoparticles as a vector for delivery. A nano-based siRNA conjugated system has been used to target various multi-drug resistance (MDR) genes of cancer to increase therapeutic specificity and control tumor progression using effective delivery. It offers a targeted avenue in gene silencing with reduced off-target effects. Pre-clinical studies show the effectiveness of this combined siRNA-nanoconjugates therapy in chemotherapeutics resistance to cancer cells. This combinatorial approach not only has the potential to induce an immune response inside the host cells but also renders the MDR genes of various cancers ineffective. The current review focuses on the effect of siRNA entry on immune cells and the factors governing them. Moreover, we have further discussed the limiting factor that controls the siRNA-nanoconjugates efficiency for effective tumor regression. We have enumerated the preclinical and clinical significance of this combined therapy for enhanced tumor regression. Furthermore, we have elaborated the impact of this combined nano-conjugated therapy host immune system while pointing out the limitations posed by them. Thus, in essence, this review provides a unique platform for the readers to understand the potential of siRNA-conjugates for anti-cancer therapy from pre-clinical to bench side.© The author(s).