Molecular-mimetic nanocolloids (MMNCs) are promising for advanced materials, yet self-assembly fabrication faces challenges in purity and programmability. We report a total synthesis strategy for surfactant-mimetic nanocolloids (SMNCs), an amphiphilic MMNC subclass. SMNCs consist of a ~5 nm silica nanoparticle head and a bottlebrush polymer tail. Regioselective silica deposition on linear-block-brush polymers via the modified sol–gel method enables precise control. This strategy is versatile and can be adapted to synthesize other MMNCs with different components. It offers a more controlled alternative to self-assembly methods, advancing MMNC synthesis and enabling their broader use in emerging technologies.