Molecular Dynamics Simulations Elucidate the Molecular Organization of Poly(beta-amino ester) Based Polyplexes for siRNA Delivery.

Cationic polymers are known to efficiently deliver nucleic acids to target cells by encapsulating the cargo into nanoparticles. However, the molecular organization of these nanoparticles is often not fully explored. Yet, this information is crucial to understand complex particle systems and the role influencing factors play at later stages of drug development. Coarse-grained molecular dynamics (CG-MD) enables modeling of systems that are the size of real nanoparticles, providing meaningful insights into molecular interactions between polymers and nucleic acids. Herein, the particle assembly of variations of an amphiphilic poly(beta-amino ester) (PBAE) with siRNA was simulated to investigate the influence of factors such as polymer lipophilicity and buffer conditions on the nanoparticle structure. Simulations were validated by wet lab methods including nuclear magnetic resonance (NMR) and align well with experimental findings. Therefore, this work emphasizes that CG-MD simulations can provide underlying explanations of experimentally observed nanoparticle properties by visualizing the nanoscale structure of polyplexes.