The design of self-assembling molecules by anionic nucleic acids and cationic polymers is of great interest in nonviral gene delivery. However, the kinetic mechanisms by which cationic polymers encapsulate anionic nucleic acids in forming polyplexes are not fully elucidated. Moreover, the complexation behavior of such polyplexes is highly dependent on several major characteristics such as molecular weight, charge density, structure of the polymer, ionic strength of buffers, and etc. Our studies examine the molecular-level kinetic mechanisms of self-assembly by PEGylated-poly(Lysine) and siRNA molecules to form polyplexes via molecular dynamics simulations using multiscale models. We also investigate the role of external biological stimuli (e.g. pH, salt concentration, PEGylated-poly(Lysine)/SiRNA concentrations, or temperature) that affect the stability and size distribution of the assembled complexes. The findings of this research will guide experimentalists in improving siRNA delivery by understanding the interactions present between anionic siRNA and cationic PEGylated-poly(Lysine) molecules and controlling the size of encapsulated complexes for gene therapy.
