Lost in Rotation: How TiO2 and ZnO Nanoparticles Disrupt Coordinated Epithelial Cell Rotation.

Coordinated cell movement is a cardinal feature in tissue organization that highlights the importance of cells working together as a collective unit. Disruptions to this synchronization can have far-reaching pathological consequences, ranging from developmental disorders to tissue repair impairment. Herein, it is shown that metal oxide nanoparticles (NPs), even at low and non-toxic doses (1 and 10 µg mL-1), can perturb the coordinated epithelial cell rotation (CECR) in micropatterned human epithelial cell clusters via distinct nanoparticle-specific mechanisms. Zinc oxide (ZnO) NPs are found to induce significant levels of intracellular reactive oxygen species (ROS) to promote mitogenic activity. Generation of a new localized force field through changes in the cytoskeleton organization and an increase in cell density leads to the arrest of CECR. Conversely, epithelial cell clusters exposed to titanium dioxide (TiO2) NPs maintain their CECR directionality but display suppressed rotational speed in an autophagy-dependent manner. Thus, these findings reveal that nanoparticles can actively hijack the nano-adaptive responses of epithelial cells to disrupt the fundamental mechanics of cooperation and communication in a collective setting.

Anisotropic hair keratin-dopamine composite scaffolds exhibit strain-stiffening properties.

Human hair keratin (HHK) has been successfully explored as raw materials for three-dimensional scaffolds for soft tissue regeneration due to its excellent biocompatibility and bioactivity. However, none of the reported HHK based scaffolds is able to replicate the strain-stiffening capacity of living tissues when responding to large deformations. In the present study, strain-stiffening property was achieved in scaffolds fabricated from HHK via a synergistic effect of well-defined, aligned microstructure and chemical crosslinking. Directed ice-templating method was used to fabricate HHK-based scaffolds with highly aligned (anisotropic) microstructure while oxidized dopamine (ODA) was used to crosslink covalently to HHKs. The resultant HHK-ODA scaffolds exhibited strain-stiffening behavior characterized by the increased gradient of the stress-strain curve after the yield point. Both ultimate tensile strength and the elongation at break were enhanced significantly (~700 kPa, ~170%) in comparison to that of HHK scaffolds lacking of aligned microstructure or ODA crosslinking. In vitro cell culture studies indicated that HHK-ODA scaffolds successfully supported human dermal fibroblasts (HDFs) adhesion, spreading and proliferation. Moreover, anisotropic HHK-ODA scaffolds guided cell growth in alignment with the defined microstructure as shown by the highly organized cytoskeletal networks and nuclei distribution. The findings suggest that HHK-ODA scaffolds, with strain-stiffening properties, biocompatibility and bioactivity, have the potential to be applied as biomimetic matrices for soft tissue regeneration.

Diatom-inspired 2D nitric oxide releasing anti-infective porous nanofrustules.

Two-dimensional (2D) nanomaterials (NM) have emerged as promising platforms for antibacterial applications. However, the inherent "flatness" of 2D NM often limits the loading of antimicrobial components needed for synergistic bactericidal actions. Here, inspired by the highly ornamented siliceous frustules of diatoms, we prepared 2D ultrathin (<20 nm) and rigid "nanofrustule" plates via the out-of-plane growth of cetyltrimethylammonium bromide (CTAB) directed silica mesostructures on the surfaces of 2D graphene oxide nanosheets. The nanofrustules were characterized by the presence of mesoporous channels with a pore size of 3 nm and a high specific surface area of 674 m2 g-1. S-nitrosothiol-modification on the silica surfaces enables the development of a novel anti-infective nitric oxide (NO) releasing NO-nanofrustule system. The cage-like mesoporous silica architecture enabled a controlled and sustainable release of NO from the NO-nanofrustules under physiological conditions. The NO-nanofrustules displayed broad antibacterial effects against Staphylococcus aureus and Escherichia coli with a minimum inhibitory concentration of 250 µg ml-1. Mechanistic studies revealed that the antibacterial property of NO-nanofrustules was attained via a unique "capture-and-release" mode-of-action. The first step entailed the capture of the bacteria by the NO-nanofrustules to form micro-aggregates. This was followed by the release of high levels of NO to the captured bacteria to elicit a potent anti-infective effect. In combination with the lack of cytotoxicity in human dermal cells, the 2D hybrid NO-nanofrustules may be utilized to combat wound infections in clinical settings.

Potent-By-Design: Amino Acids Mimicking Porous Nanotherapeutics with Intrinsic Anticancer Targeting Properties.

Exogenous sources of amino acids are essential nutrients to fuel cancer growth. Here, the increased demand for amino acid displayed by cancer cells is unconventionally exploited as a design principle to replete cancer cells with apoptosis inducing nanoscopic porous amino acid mimics (Nano-PAAM). A small library consisting of nine essential amino acids nanoconjugates (30 nm) are synthesized, and the in vitro anticancer activity is evaluated. Among the Nano-PAAMs, l-phenylalanine functionalized Nano-PAAM (Nano-pPAAM) has emerged as a novel nanotherapeutics with excellent intrinsic anticancer and cancer-selective properties. The therapeutic efficacy of Nano-pPAAM against a panel of human breast, gastric, and skin cancer cells could be ascribed to the specific targeting of the overexpressed human large neutral amino acid transporter SLC7A5 (LAT-1) in cancer cells, and its intracellular reactive oxygen species (ROS) inducing properties of the nanoporous core. At the mechanistic level, it is revealed that Nano-pPAAM could activate both the extrinsic and intrinsic apoptosis pathways to exert a potent "double-whammy" anticancer effect. The potential clinical utility of Nano-pPAAM is further investigated using an MDA-MB-231 xenograft in NOD scid gamma mice, where an overall suppression of tumor growth by 60% is achieved without the aid of any drugs or application of external stimuli.