The Spatial Distribution of Lipophilic Cations in Gradient Copolymers Regulates Polymer-pDNA Complexation, Polyplex Aggregation, and Intracellular pDNA Delivery.

Here, we demonstrate that the spatial distribution of lipophilic cations governs the complexation pathways, serum stability, and biological performance of polymer-pDNA complexes (polyplexes). Previous research focused on block/statistical copolymers, whereas gradient copolymers, where the density of lipophilic cations diminishes (gradually or steeply) along polymer backbones, remain underexplored. We engineered gradient copolymers that combine the polyplex colloidal stability of block copolymers with the transfection efficiency of statistical copolymers.

Poly(l-glutamic acid) augments the transfection performance of lipophilic polycations by overcoming tradeoffs among cytotoxicity, pDNA delivery efficiency, and serum stability.

Polycations are scalable and affordable nanocarriers for delivering therapeutic nucleic acids. Yet, cationicity-dependent tradeoffs between nucleic acid delivery efficiency, cytotoxicity, and serum stability hinder clinical translation. Typically, the most efficient polycationic vehicles also tend to be the most toxic.