Nonviral gene delivery vectors are attractive candidates compared to viral ones due to their lower cytotoxicity and immunogenicity. However, their efficacy still requires improvement. Major challenges are the effective complexation and protection of the DNA cargo and the intracellular dissociation of the polyplexes at the site of action. It is commonly accepted that polymer architecture and chemistry influence polyplex characteristics and have an impact on the transfection mechanism. We developed a library of biocompatible copolymers based on methoxy poly(ethylene glycol) and a hydrophobic block of poly(ε-caprolactone-co-propargyl carbonate) grafted with a predetermined number of poly(2-(dimethylamino)ethyl methacrylate) segments. Such copolymers could efficiently deliver their cargo even in the presence of serum proteins and to various "difficult to transfect" cells, thereby outperforming the current gold standard 25 kDa linear poly(ethylenimine). Statistical correlation analysis shows that an optimization of the transfection in the case of copolymers combining several interactive functions benefits from treatment as a multiparameter problem.