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The size and structure of inorganic fillers have a significant effect on the mechanical properties of dental resin composites. In this work, we report the use of spray-drying for the efficient construction of SiO2 colloidal nanoparticle clusters (SCNCs) as novel dental fillers, yielding spherical and closely packed structures with diameters of 1–3 μm. The superior performance of the resin composites can be obtained by filling 70 wt % SCNCs assembled with 60 nm silica colloids as building blocks in the dental resin matrix. As compared to silica microparticles with a similar average size and primary monodispersed silica nanoparticles, SCNCs have a better strengthening effect on the mechanical properties of resin composites owing to their unique nano–micro secondary structures. This spray-drying strategy enables the construction of multicomponent fillers. This is very promising for the development of multifunctional high-performance restorative resin composites.