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Clift et al. Theranosticnanoparticlesand thebloodstream regard, it is also relevant to highlight that a series of other exposure routes, includ- ing ingestion, cutaneous and inhalation (Melancon et al., 2012), the latter for which theranostic applications are being derived (Pison et al., 2006), also pose a potential access route for NPs into the blood circulation via translocation across cellular barriers (Kreyling et al., 2012). Furthermore, the use of NPs to coat implants (i.e., for antimicrobial purposes) hasrecentlyincreased(Kempeetal.,2010), and therefore it is possible that these could further concentrate the NPs gain- ing access into the human bloodstream, also viabarrier cell translocation. Yet, the presence of NPs within the bloodstream from these exposure routes represents a secondary, non-specific exposure scenario and relates to a risk perspective. Whilst risk assessment is not the purpose of this article, it is worth to highlight that this issue has received limited attention to date, and requires further, in-depth investigationwhich could advantageously coincide with the advancement of NPs fornanomedicine-basedapplications (i.e., understanding theirbiocompatibility). MOVINGFORWARD Due to the lack of an advanced in vitro model system, as previously highlighted, determiningtheroleofeachcomponentof the bloodstreamas to its potential impact upon theranostic NPs is imperative to theiroveralldevelopment.Howeverwhich constituentsare important? Mostnotably, theimmediateandabun- dant adherence of proteins (as well as lipids) to the surface of any theranos- tic NPs entering the bloodstream (Lynch et al., 2006) can create a possible issue towards the surface molecules attached for a specific therapeutic purpose (i.e., receptor-binding sequence), as well as a lossincolloidalstabilityduetoaggregation (Hirsch et al., 2014). AlthoughNPs with varying physico-chemical characteristics can be manipulated for nanotheranos- tics, it has become abundantly apparent thatsimilarproteinsareconsistentlyfound upon the surface of NPs independent of their surface coating/charge (Hirsch et al., 2013). Whilst this is a dynamic process upon the surface ofNPs, there remains a hard protein layer on top of the NPs at all times, thus posing a significant issue to material scientists. Yet, if coated with abundant proteins, these can engagewith the epitopes on the immune cells, and so it isdifficult todecipher if thesteric repul- sive barrier of a polymer shell would still remaineffective enoughtopreventuptake bythesephagocyticcells,ornot.Although, if internalizedby the immune system,will they be processed and potentially exocy- tosed by these cell types, and exhibit the same properties prior to their adminis- tration?What the physico-chemical state of the NPs is following this interac- tion is currently unknown, and requires in-depth investigation. If however, the immune system does not recognize the NPs, then there is a heightened possibil- ity that they could pass, unimpeded into erythrocytes (Rothen-Rutishauser et al., 2006). The impact that this cellular inter- actionmayhaveupontheNPs is relatively unknown. Although if the NPs become presentwithin these cell types, circulation time(of theNPs)willmost likely increase, perhaps rendering themineffectiveand/or aggregating within the bloodstream with potentialadverse/fatalconsequences inthe long-term. In addition to these cellu- lar/molecule based issues, the effect of the injection process (e.g., pressure, flow- rate, pH and temperature changes) upon thephysico-chemical characteristicsof the NPs via their administration route must also be conceived. Therefore, increased researchstrategiesmustbedirectedtoward this approach to achieve the successful developmentof theranosticNPs. OVERALLPERSPECTIVE Due to their inevitable administration to the human body via intravenous injec- tion, understanding of the interaction of theranostic NPs with the complex bio- logical environment of the bloodstream is vital in regards to their development. Theknowledgecreatedfromthisapproach could enable key understanding to be gained as to the ability for the NPs to withstand the confines of this local environment. Furthermore, it will pro- vide imperative insight into their abil- ity to effectively perform the task they were engineered to achieve (e.g., drug delivery). Since following this approach the NPs will most likely require fur- ther manipulation regarding their physi- cal and chemical characteristics, in order to achieve this outlook an enhanced, multi-interdisciplinary approachmust be adopted. By combining the expertise of a variety of disciplines it will enable the advancement of systematic studies of the physical and chemical state of the NPs based on the impact observed when NPs are present within the bloodstream. Therefore, this perspective will facilitate theessentialdevelopment required tosuc- cessfullymanufactureeffective theranostic NPs forhumanhealthcare. ACKNOWLEDGMENTS The authors would like to thank the generous research funding received from the Swiss National Science Foundation(Grant#310030_156871/1;# 406440-131264/1; # PP00P2_123373; # 320030_138365), the Swiss National Science Foundation through theNational Centre of Competence in Research Bio-Inspired Materials and by the Competence Centre forMaterials Science and the Adolphe Merkle Foundation. The authors also thank the members of the BioNanomaterials group at the Adolphe Merkle Institute for scientific discussions. REFERENCES Abbas, A. K., and Lichtman, A. H. (2003). Cellular andMolecular Immunology. Oxford, UK: Elsevier Science. BSI. (2007).PubliclyAvailableSpecification(PAS)136. Terminology forNanomaterials. Capco, D., and Chen, Y. (2014). Nanomaterials: Impacts on Cell Biology andMedicine. Dordrecht: Springer. Davis, M. E., Chen, Z., and Shin, D. M. (2008). Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. 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