The formation of protein corona (PC) around nanoparticles (NPs) has been reported inside biological conditions. This effect can alter delivery capacity toward the targeted tissues. Here, we synthesized folic acid-modified chitosan NPs (FA-CS NPs) using different concentrations of folic acid (5, 10, and 20%). FA-CS NPs were exposed to plasmas of breast cancer patients and healthy donors to evaluate the possibility of PC formation. We also monitored uptake efficiency in conditions after incubation with human breast cancer cell line MDA-MB-231 and monocyte/macrophage-like Raw264.7 cells. Data showed that the formation of PC around FA-CS NPs can change physicochemical properties coincided with the rise in NP size and negative surface charge. SDS-PAGE electrophoresis revealed differences in the type and content rate of plasma proteins attached to NP surface in a personalized manner. Based on MTT data, the formation of PC around NPs did not exert cytotoxic effects on MDA-MB-231 cells while this phenomenon reduced uptake rate. Fluorescence imaging and flow cytometry analyses revealed reduced cellular internalization rate in NPs exposed to patients' plasma compared to the control group. In contrast to breast MDA-MB-231 cells, Raw264.7 cells efficiently adsorbed the bare and PC-coated NPs from both sources, indicating the involvement of ligand-receptor-dependent and independent cellular engulfment. These data showed that the PC formed on the FA-CS NPs is entirely different in breast cancer patients and healthy counterparts. PC derived from patients' plasma almost abolishes the targeting efficiency of FA-CS NPs even in different mechanisms, while this behavior was not shown in the control group. Surprisingly, Raw264.7 cells strongly adsorbed the PC-coated NPs, especially when these particles were in the presence of patients' sera. It is strongly suggested that the formation of PC around can affect delivering capacity of FA-CS NPs to cancer cells. It seems that the PC-coated FA-CS NPs can be used as an efficient delivery strategy for the transfer of specific biomolecules in immune system disorders.