Successful gene therapies require the efficient delivery of the therapeutic nucleic acids in the target cells, which is a major bottleneck. Our group has demonstrated that quinine-based polymers are effective and promising carriers for delivering nucleic acids, such as plasmid DNA (pDNA). However, the inherent hydrophobicity of quinine-based polymers makes the polymer-pDNA complexes (polyplexes) colloidally unstable leading to aggregation, which is relevant in clinical scenarios as larger particles (diameter >
1000 nm) tend to perform poorly when administered systemically in vivo. Herein, we overcome the hydrophobicity-induced aggregation by using two types of quinine-based polymer systems to form polyplexes via a facile blending approach. We balanced desirable properties using quinine-based copolymers (HQ-