The potential of gene therapy for the treatment for chronic and life-threatening diseases has been seen for a long time, but widespread applications are still hampered by the difficulties to deliver the highly charged and large nucleic acid molecules to their intracellular targets. More recently, investigators have been aiming for local delivery of nucleic acids mostly by the use of hydrogels. In this way, in vivo efficacy can be enhanced by avoiding the target transport challenges and at the same time limit off-target effects. In these systems, nucleic acids are entrapped within hydrogels, either as conjugates or as polyplex particles, for local and controlled release. There are numerous design features in the selection of polymers, for both particle and hydrogel formation that should be considered to achieve efficient local nucleic acid delivery. Therefore, this review focusses on the rational design of polymeric and hydrogel materials for local gene therapy applications.