Nanoparticle (NP) effects in a biological system are driven through the formation and structure of the protein corona-NP complex, which is dynamic by nature and dependent upon factors from both the local environment and NP physicochemical parameters. To date, considerable data has been gathered regarding the structure and behavior of the protein corona in blood, plasma, and traditional cell culture medium. However, there exists a knowledge gap pertaining to the protein corona in additional biological fluids and following incubation in a dynamic environment. Using 13nm gold NPs (AuNPs), functionalized with either polyethylene glycol or tannic acid, we demonstrated that both particle characteristics and the associated protein corona were altered when exposed to artificial physiological fluids and under dynamic flow. Furthermore, the magnitude of observed behavioral shifts were dependent upon AuNP surface chemistry. Lastly, we revealed that exposure to interstitial fluid produced protein corona modifications, reshaping of the nano-cellular interface, modified AuNP dosimetry, and induction of previously unseen cytotoxicity. This study highlights the need to elucidate both NP and protein corona behavior in biologically representative environments in an effort to increase accurate interpretation of data and transfer of this knowledge to efficacy, behavior, and safety of nano-based applications.

Chronic traumatic encephalopathy (CTE) is associated with repeated traumatic brain injuries (TBI) and is characterized by cognitive decline and the presence of neurofibrillary tangles (NFTs) of the protein tau in patients’ brains. Here we provide direct evidence that cell-scale mechanical deformation can elicit tau abnormalities and synaptic deficits in neurons. Using computational modeling, we find that the early pathological loci of NFTs in CTE brains are regions of high deformation during injury. The mechanical energy associated with high-strain rate deformation alone can induce tau mislocalization to dendritic spines and synaptic deficits in cultured rat hippocampal neurons. These cellular changes are mediated by tau hyperphosphorylation and can be reversed through inhibition of GSK3β and CDK5 or genetic deletion of tau. Together, these findings identify a mechanistic pathway that directly relates mechanical deformation of neurons to tau-mediated synaptic impairments and provide a possibly exploitable therapeutic pathway to combat CTE.

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The incorporation of engineered nanoparticles (NPs) into everyday consumer goods, products, and applications has given rise to the field of nanotoxicology, which evaluates the safety of NPs within biological environments. The unique physicochemical properties of NPs have made this an insurmountable challenge, as their reactivity and variable behavior have given rise to discrepancies between standard cell-based in vitro and animal in vivo models. In this study, enhanced in vitro models were generated that retained the advantages of traditional cell cultures, but incorporated the modifications of (1) inclusion of an activated immune element and (2) the presence of physiologically-relevant dynamic flow. Following verification that the human alveolar epithelial and macrophage (A549/U937) co-culture could be successfully sustained under both static and dynamic conditions, these cultures, in addition to a standard A549 static model, were challenged with 10 nm citrate coated silver NPs (AgNPs). This work identified a reshaping of the AgNP-cellular interface and differential biological responses following exposure. The presence of dynamic flow modified cellular morphology and reduced AgNP deposition by approximately 20% over the static exposure environments. Cellular toxicity and stress endpoints, including reactive oxygen species, heat shock protein 70, and secretion of pro-inflammatory cytokines, were found to vary as a function of both cellular composition and flow conditions; with activated macrophages and fluid flow both mitigating the severity of AgNP-dependent bioeffects. This work highlights the possibility of enhanced in vitro systems to assess the safety of engineered NPs and demonstrates their effectiveness in elucidating novel NP-cellular interactions and toxicological profiles.