Nanoparticles (NPs) can be harnessed for a variety of applications in the biomedical field, taking advantage of their size range which is 1–100 nm. Conventional formulations possess many pitfalls as they interact with the biomolecules and their efficiency or activity is largely affected. This points out the importance of the study of the interactions between the drugs and the biomolecules and the possible outcomes. As with any other drug molecules, the NPs’ interaction with the body and biomolecules is also to be studied intensively for the same reason, to obtain the maximum therapeutic efficacy and minimize the toxic effects. The changes happening to the NPs can influence their biological fate like absorption, therapeutic action, eliciting an immune response, or their clearance from the body. Nanocorona (NC) formation over the surface of the NPs by biomolecules is one of the major events happening during their course inside the body. This property influences their interaction with the various components of the innate immune system, biological activity, and toxicity as well. The recent advancements in nanotechnology enabled the production of engineered NPs which can not only elicit an immunological reaction but also can be used for immunosuppression. This reflects the immunity-switching capability of the NPs which can be used for the treatment of many immunological diseases. The NPs are capable of interfering with the neuroimmune crosstalk, which is believed to be a governing factor in the development and progression of diseases such as cancer, stroke, mood disorders, multiple sclerosis, and many others. In general, if the NPs are detected by the phagocytes of the immune system, they are rapidly cleared from the body resulting in therapeutic failure. This indicates the significance of understanding the mechanisms of interaction of NPs with the immune system, along with the possibilities of altering the structure of NC to tune their properties. In this chapter, we have reviewed the significance of NC and how it influences neuroimmune communications, which can be harnessed for novel treatment methods for several diseases.