Nowadays, nanodrugs become a hotspot in the high-end medical field. They have the ability to deliver drugs to reach their destination more effectively due to their unique properties and flexible functionalization. However, the fate of nanodrugs in vivo is not the same as those presented in vitro, which indeed influenced their therapeutic efficacy in vivo. When entering the biological organism, nanodrugs will first come into contact with biological fluids and then be covered by some biomacromolecules, especially proteins. The proteins adsorbed on the surface of nanodrugs are known as protein corona (PC), which causes the loss of prospective organ-targeting abilities. Fortunately, the reasonable utilization of PC may determine the organ-targeting efficiency of systemically administered nanodrugs based on the diverse expression of receptors on cells in different organs. In addition, the nanodrugs for local administration targeting diverse lesion sites will also form unique PC, which plays an important role in the therapeutic effect of nanodrugs. This article introduced the formation of PC on the surface of nanodrugs and summarized the recent studies about the roles of diversified proteins adsorbed on nanodrugs and relevant protein for organ-targeting receptor through different administration pathways, which may deepen our understanding of the role that PC played on organ-targeting and improve the therapeutic efficacy of nanodrugs to promote their clinical translation.