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Nucleic acids have immense potential for the treatment and prevention of a wide range of diseases, but delivery vehicles are needed to assist with their entry into cells. Polycations can reversibly complex with nucleic acids via ionic interactions to form polyplexes and transport them into cells, but they are still hindered by the need to balance cytotoxicity and delivery effectiveness. In this work, we describe a new self-immolative polyglyoxylamide (PGAm) platform designed to address these challenges by complexing nucleic acids viamultivalent interactions in the polymeric form and releasing them upon depolymerization. Nine PGAms were synthesized and characterized, with different end-caps and variable cationic pendent groups. The PGAms underwent depolymerization under mildly acidic conditions, with rates dependent on their pendent groups and end-caps. They complexed plasmid DNA, forming cationic nanoparticles, and released it upon depolymerization. Cytotoxicity assays of the PGAms and polyplexes in HEK 293T cells showed a decrease in toxicity following depolymerization, and all samples exhibited much lower toxicity than a commercial non-degradable linear polyethyleneimine (jetPEI) transfection agent. Transfection assays revealed that selected PGAms provided similar levels of reporter gene expression to jetPEI in vitro with a PGAm analogue of poly[2-(dimethylamino)ethyl methacrylate] having particularly interesting activity that was dependent on depolymerization, along with low cytotoxicity. Overall, these results indicate that end-to-end depolymerization of self-immolative polymers can provide a new and promising tool for nucleic acid delivery.