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Once introduced into physiological environment, nanoparticles (NPs) are immediately coated with proteins, resulting in formation of what is known as protein corona. The formation of protein corona can be affected by many factors. Likewise, the addition of protein corona can alter the physicochemical properties and biodistribution of NPs. NPs with the coating protein corona can be considered as a biological identity that recognized by cells in biological system. Thus, to understand and regulate the effect of protein corona on targeting capability of NPs in vivo, it is necessary to elucidate the interaction between the NPs and the biological fluid. In this review, we first elucidate the factors influencing the formation of protein corona, including NPs physicochemical factors, such as NPs composition, size, shape, surface chemistry, etc., and environmental factors, such as environmental temperature, protein origins, etc. Then, we focus on the effect of protein corona on the passive targeting and active targeting, and discuss the probable reasons that causing the discrepant results. Finally, we review the strategies for tuning the protein corona to promote targeting, including reducing protein adsorption and recruiting specific proteins.