Abstract: A synthesis method of a targeted drug nCoVshRNA.2ACE2 of a COVID-19 virus, which includes the following steps: designing a consensus RNAi sequence siRNA of the COVID-19 virus and a variant strain thereof; synthesizing two complementary siRNAs into a small hairpin-shaped shRNA with a loop, and synthesizing ACE2 or a cell penetrating peptide ACE2 with a receptor-binding domain (RBD) as a ligand; and ligating the ACE2 to a sense strand and an antisense strand of the shRNA separately to synthesize the nCoVshRNA.2ACE2 including a shRNA region and an ACE2 region. The bivalent ACE2 functions to neutralize the RBD and deliver the shRNA in a targeted manner; an “shRNA-ACE2-RBD-virus” complex bridged by the ACE2 allows the shRNA to enter target cells with virus infection, thereby avoiding a side effect of non-specific delivery of the shRNA to uninfected cells, as well as resisting the variant strain and neutralizing the virus with the ACE2.