The selective interaction of nanomaterials with proteins for protein function suppression has been reported. However,whether the nanomaterials could be used to target a three-dimensional (3D) structure of proteins for the consequent function inhibition is not defined. When SARS-CoV-2 binds to the host cell surface ACE2 receptor,the spike protein trimer changes to an"Open State"which forms a 5 nm cavity structure,consequently exposing the receptor binding domain (RBD) for the following viral infection. We found that the 3 nm cerium oxide nanoparticles (CeO2@3) showed a better anti-SARS-CoV-2 effect than 30 nm cerium oxide nanoparticles (CeO2@30). We performed a series of experiments and demonstrated that the CeO2@3 could target the 5 nm spike protein trimer cavity and tightly bind with the RBD,thus effectively blocking the following virus-cell interaction and rendering CeO2@3 as an effective anti-viral agent. As all coronaviruses possess similar spike protein structures as homologous proteins,CeO2@3 can be used as a broad-sperm anti-coronavirus nanodrug candidate by targeting the spike protein 3D structure. This work,for the first time,demonstrated that rationally engineered inorganic nanomaterials can be used to specifically target a 3D structure of a certain protein for function inhibition,thus providing a novel methodological approach and paving the way for future molecular targeting nanodrug candidate design.