Molecular Insights into the Bio-oligomer Complexation with siRNA toward Therapeutic Applications

Small interfering RNA (siRNA) holds immense potential as a therapeutic agent for treating complex diseases such as cancer, cardiovascular ailments, neurodegenerative conditions, and inflammatory disorders owing to its high target specificity and low dose requirements. However, its clinical translation is challenged by structural (negative charge and high molecular weight) and functional (short half-life and off-targeting) limitations, necessitating an effective carrier for targeted delivery. Biocompatible and biodegradable materials are key to the development of efficient siRNA delivery systems. This study employs molecular dynamics (MD) simulations to investigate the complexation of atomistically modeled siRNA with <i>N</i>-acryloyl-phenylalanine methyl ester (NAPA) oligomers, chosen for their biocompatibility, drug encapsulation potential, and adjuvant properties. Oligomers ranging from monomers to pentamers were studied in complex with 22-mer siRNA in aqueous solution to understand binding mechanisms on the molecular scale. Key structural and dynamical parameters─such as groove width, contact number, hydrogen bonding, radial distribution function, solvent accessibility, root-mean-square fluctuation, and pair correlation entropy─were analyzed. Stable siRNA-oligomer complexes formed within 20 ns, driven largely by hydrogen bonding interactions within siRNA grooves. The binding followed Langmuir first-order adsorption kinetics, with 28, 17, 16, 12, and 11 oligomers attaching to siRNA for monomer to pentamer, respectively. Among them, the siRNA-pentamer complex showed the greatest compaction (∼18%) and stability. These findings highlight the potential of NAPA oligomers as effective carriers for siRNA, offering valuable insights for the design of targeted delivery systems in RNA-based therapies.