Nanomedicine is recognized as a promising agent for diverse biomedical applications; however, its safety and efficiency in clinical practice remains to be enhanced. A priority issue is the protein corona (PC), which imparts unique biological identities to prototype and determines the actual biological functions in biological fluids. Decades of work has already illuminated abundant considerations that influence the composition of the protein corona. Thereinto, the physical assets of nanomedicines (e.g., size and shape, surface properties, nanomaterials) and the biological environment collectively play fundamental roles in shaping the PC, including the types and quantities of plasma proteins. The properties of nanomedicines are dependent on certain factors. This review aims to explore the applications of nanomedicines by regulating their interplay with PC.