Genetic disorders are conditions caused by DNA alterations that affect cell structure and functionality. Gene therapy represents a potential innovative approach aimed at directly correcting the underlying genetic mutations. However, one of the main challenges of gene therapy is ensuring the safe and effective delivery of therapeutic genes to target cells. The purpose of this project was to assess the potential of bioerodible, injectable, and supramolecular (SM) hydrogels as carriers for the localized release of siRNA-containing polyplexes (PXs). SM hydrogels were designed by mixing aqueous solutions of a custom-synthesized amphiphilic Poloxamer®407-based poly(ether urethane) (PEU) and commercial α-cyclodextrins (α-CDs). In the final formulations, PEU and α-CDs concentration varied in the range 1.43%-2.57% w/v and 8.56%-10% w/v, respectively.