Toxicity and health impact of nanoparticles. Basic biology and clinical perspective.

Stroke has limited restorative treatment options. In search of new therapeutic strategies for the ischemic brain, cell-based therapies offered new hope, which has been, in the meanwhile, converted into a more realistic approach recognizing difficulties related to unfavorable environments causing low survival rates of transplanted neuronal precursors. Stem cell therapies are based on the transplantation of neuronal precursor cells (NPCs), adult stem cells propagated in cell culture or inducible pluripotent cells (iPSCs) obtained from patients and trans-differentiated into neural cells. Of these, autologous iPSCs have the advantage to be used in stroke patients because they do not raise ethical concerns and the risk of graft rejection is low. However, the use of stem cells for stroke therapy in humans has to take into account many factors including, dosage, route of administration, toxicity and side effects. For example, nanoparticles (NPs) may increase the efficacy of drugs and therapeutic cells delivery to the diseased brain. Medication dosages are generally determined by clinical trials done in relatively young, healthy people. However, in vivo and clinical data evaluating the toxic effects of NPs on neural cells are still scarce especially in the aged brain, which has a decreased homeostatic capacity and a reduced ability to cope with internal and environmental stress, as compared to the young brain. Previous studies in rodents indicate that aging along with neurodegenerative diseases may promote a proinflammatory state and leads to the development of gliosis in the aged brains. On the other hand, the nonspecific interaction between the shell of NPs and brain proteins leads to the adsorption of opsonins on their surface, forming the so-called "corona", thereby becoming ideal candidates to attract phagocytic microglia resulting in NPs engulfment and thus exacerbating neuronal death. Therefore, when designing NPs for clinical use, it should be considered that their systemic administration is associated with potential risks, especially in the aged subjects. Recently, NPs have been shown in recent years to play a crucial role in cell signaling processes involved in stroke recovery. Extracellular vesicles (EVs) are secreted by virtually all type of cells in the body and have been shown to reflect the physiological and metabolic status of the host cells. Thus, understanding the disease-specific contents of EVs would enable the discovery of novel predictive biomarkers.