Macromolecular nucleic acids such as DNA vaccines, siRNA, and splice-site switching oligomers (SSO) have vast chemotherapeutic potential. Nanoparticulate biomaterials hold promise for DNA and RNA delivery when a means for binding is identified that retains structure-function and provides stabilization by the nanoparticles. In order to provide these benefits of binding, we combined DNA and RNA with protamine-demonstrating association to gold microparticles by electrophoretic, gel shot, fluorescence, and dynamic laser light spectroscopy (DLLS). A pivotal finding in these studies is that the Au-protamine-DNA conjugates greatly stabilize the DNA; and DNA structure and vaccine activity are maintained even after exposure to physical, chemical, and temperature-accelerated degradation. Specifically, protamine formed nanoparticles when complexed to RNA. These complexes could be detected by gel shift and were probed by high throughput absorbance difference spectroscopy (HTADS). Biological activity of these RNA nanoparticles (RNPs) was demonstrated also by a human tumor cell splice-site switching assay and by siRNA delivery against B-Raf-a key cancer target. Finally, RNA:protamine particles inhibited growth of cultured human tumor cells and bacteria. These data provide new insights into DNA and RNA nanoparticles and prospects for their delivery and chemotherapeutic activity.