In the last years, two decades after its discovery, siRNA has finally completed its path from bench to bedside and its use is now expected to be extended to a growing number of diseases. Nevertheless, siRNA application is still limited by the barriers it has to face in the human body, hindering its efficacy. Several strategies have been investigated to overcome these barriers and many are still in a developmental stage: polymer and lipid based formulations are two of the main approaches currently used to effectively shield and deliver nucleic acids to targeted cells. However, both of them still have weaknesses, such as toxicity or instability, limiting the high potential of siRNA therapies.