Comprehensive Summary Aiming to the enormous requirement for the epidemic defense researches, we designed and constructed a spherical colloidal virus particle (CVP) to mimic nature virus in morphology, physical, chemical and biological characteristics, via coating spiky protein on colloidal nanoparticles (CNPs) core with bulge hierarchical nanomorphology. The novel virus‐like surface nanoparticles can easily be synthesized. The physical, chemical nature and the formation mechanism of the prepared CVPs were characterized and discussed. The synthesized CVPs are similar in size and envelope thickness to common natural viruses. It was demonstrated that the diameter of CVPs is about 238 ± 12 nm, including an 8 nm thickness protein crown with bulges of 33 nm in average width. The CVPs with an isoelectric point of 4.5, meets the native virus property of negative charge under neutral condition. The protein crown enhances the roughness remarkably from 10 nm (CNPs) to 22 nm (CVPs) determined by atomic force microscopy. Thanks to the biomimetic rough morphology, the CVPs show greatly superior cellular uptake performance compared to CNPs, ovalbumin (OVA) and smoothed colloidal particles (SCPs). The formation mechanism of protein crown with specific thickness can be attributed to the electrostatic interaction, protein's flexible structure and specific wettability. These results indicate that the as‐prepared artificial virions mimic nature viruses in multi‐dimension, in terms of size, surface rough morphology, surface negative charge and glycoprotein envelope composition. The synthetic colloidal virus particles pave a facile way toward engineering virus particles substitute for virus‐related diseases prevention, diagnostics and cellular delivery vectors.