Ligand-mediated interface control has been broadly applied as a powerful tool in constructing sophisticated nanocomposites. However, the resultant morphologies are usually limited to solid structures. Now, a facile spatially controllable ligand-mediated superassembly strategy is explored to construct monodispersed, asymmetric, hollow, open Au-silica (SiO2) nanotadpoles (AHOASTs). By manipulating the spatial density of ligands, the degree of diffusion of silica can be precisely modulated; thus the diameters of the cavity can be continuously tuned. Due to their highly anisotropic, hollow, open morphologies, we construct a multicompartment nanocontainer with enzymes held and isolated inside the cavity. Furthermore, the resulting enzyme-AHOASTs are used as biocompatible smart H2O2-sensitive nanoswimmers and demonstrate a higher diffusion coefficient than other nanoscaled swimmers. We believe that this strategy is critical not only in designing sophisticated hollow nanosystem but also in providing great opportunities for applications in nanomaterial assembly, catalysis, sensors, and nanoreactors.