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Evaluation of systemic biosafety of nanomaterials urgently demands a comprehensive understanding of the mechanisms of the undesirable interference and systemic signaling that arises between man-made nanomaterials and biological systems. It is shown that exosomes may act as signal conveyors for nanoparticle-induced systemic immune responses. Exosomes are extracellularly secreted membrane vesicles which act as Trojan horses for the dissemination and intercellular communication of natural nanosized particles (like viruses). Upon exposure to magnetic iron oxide nanoparticles (MIONs), it is possible to dose-dependently generate a significant number of exosomes in the alveolar region of BALB/c mice. These exosomes are quickly eliminated from alveoli into systemic circulation and largely transfer their signals to the immune system. Maturation of dendritic cells and activation of splenic T cells are significantly induced by these exosomes. Furthermore, exosome-induced T-cell activation is more efficient toward sensitized T cells and in ovalbumin (OVA)-sensitized mice than in the unsensitized counterparts. Activation of systemic T cells reveals a T helper 1 polarization and aggravated inflammation, which poses potential hazards to the deterioration of allergic diseases in OVA-sensitized mice. The studies suggest that exosomes may act as conveyors for extrapulmonary signal transduction in nanoparticle-induced immune systemic responses, which are the key in vivo processes of manufactured nanoparticles executing either biomedical functions or toxic responses.