RNA interference is currently one of the most advanced genomic tools providing promising insight to manage countless pathophysiological conditions that seemed unapproachable few years ago. Researchers across the globe have devised numerous methods in which small RNA molecules can be administered into target cells to manipulate cellular functions at the molecular level and eradicate defects that lead to pronounced phenotypes, which might sometimes be as fatal as malignant tumors. The present review provides an overview of the non-viral delivery approaches for siRNA therapeutics with an emphasis on the PLGA polymeric strategy and its use in different biological applications. Due to its versatile surface, PLGA is not only used in tissue engineering such as remodeling of bone and cartilage, but it indeed plays a crucial role as chemical carrier for a broad range of therapeutic agents. It is greatly implicated in gene therapies and inherited genetic defects.