A variety of delivery vehicles use spermine as a polycationic component to form complexes with nucleic acids. Thus, we investigated the influence of molecular architecture, amine density, and molecular weight of oligospermines on its binding to nucleic acids. We report the synthesis of mono, bis, and tetraspermines with linear, cyclic, dendritic, and quatrefoil architecture. The effect of molecular weight was more pronounced in linear oligospermines than their cyclic counterparts. Oligospermines with similar amine density but different molecular architectures exhibited different binding profiles. Among all oligospermines evaluated, dendritic tetraspermine exhibited the highest binding affinity. Atomistic molecular dynamics simulations also indicated higher affinity for dendritic tetraspermine to siRNA than its linear counterpart suggesting the importance of spermine geometry in binding to nucleic acids. Importantly, dendritic tetraspermine was less toxic than linear tetraspermine, suggesting its potential in nucleic acid delivery.