Spheres-on-sphere (SOS) silica particles are prepared in a one-pot scalable synthesis from mercaptopropyltrimethoxysilane with hydrophilic polymer and cationic surfactant under alkaline conditions. The SOS particles exhibit solid-core porous-shell properties. The fast separation of small molecules and proteins with low back pressure are demonstrated by high-performance liquid chromatography (HPLC) for the columns packed with SOS-particles. [GRAPHICS] .