Gene technology is facing years of crucial development with the promise of bringing new opportunities for the treatment of several diseases, targeting the causes instead of the symptoms. However, finding a proper delivery vehicle able to overcome the countless barriers present in the physiological environment is still the main challenge, that needs to be addressed to improve the clinical translation. Local nucleic acid delivery allows to reduce the doses, obstacles, and side effects. The present work represents an exploratory study with the main goal of finding out whether a well-established injectable and bioerodible supramolecular (SM) hydrogel based on a customized poly(ether urethane) (PEU) and α-cyclodextrins (CDs) could be used as a platform for the localized delivery of polyethylenimine/small interfering RNA (PEI/siRNA) polyplexes.