Tackling the Limitations of Copolymeric Small Interfering RNA Delivery Agents by a Combined Experimental-Computational Approach.

Despite the first successful applications of nonviral delivery vectors for small interfering RNA in the treatment of illnesses, such as the respiratory syncytial virus infection, the preparation of a clinically suitable, safe, and efficient delivery system still remains a challenge. In this study, we tackle the drawbacks of the existing systems by a combined experimental-computational in-depth investigation of the influence of the polymer architecture over the binding and transfection efficiency. For that purpose, a library of diblock copolymers with a molar mass of 30 kDa and a narrow dispersity (Đ < 1.12) was synthesized. We studied in detail the impact of an altered block size and/or composition of cationic diblock copolymers on the viability of each respective structure as a delivery agent for polynucleotides. The experimental investigation was further complemented by a computational study employing molecular simulations as well as an analytical description of systemic properties. This is the first report in which molecular dynamics simulations of RNA/cationic polymer complexes have been performed. Specifically, we developed and employed a coarse-grained model of the system at the molecular level to study the interactions between polymer chains and small interfering RNA. We were further able to confirm a threshold length