INMdok (Leibniz Institute for New Materials)
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Dynamic fine-tuning of CAR-T cell therapy
Get PDFCancer immunotherapy has transformed cancer treatment, with chimeric antigen receptor (CAR)-T cell therapy being one of the most promising approaches. In the previous issue of Molecular Therapy – Oncolytics, Lainšček et al.1 outline a novel strategy for controlling CD19 CAR-T cell activity to address limitations currently hampering clinical practice. To better and dynamically align CAR-T cell activity with clinical needs, the authors developed a method for external control based on engineered endogenous transcription factors acting downstream of the CAR signaling pathway
Light-Regulated Pro-Angiogenic Engineered Living Materials
Get PDFRegenerative medicine aims to restore damaged cells, tissues, and organs, for which growth factors are vital to stimulate regenerative cellular transformations. Major advances have been made in growth factor engineering and delivery like the development of robust peptidomimetics and controlled release matrices. However, their clinical applicability remains limited due to their poor stability in the body and need for careful regulation of their local concentration to avoid unwanted side-effects. In this study, a strategy to overcome these limitations is explored using engineered living materials (ELMs), which contain live microorganisms that can be programmed with stimuli-responsive functionalities. Specifically, the development of an ELM that releases a pro-angiogenic protein in a light-regulated manner is described. This is achieved by optogenetically engineering bacteria to synthesize and secrete a vascular endothelial growth factor peptidomimetic (QK) linked to a collagen-binding domain. The bacteria are securely encapsulated in bilayer hydrogel constructs that support bacterial functionality but prevent their escape from the ELM. In situ control over the release profiles of the pro-angiogenic protein using light is demonstrated. Finally, it is shown that the released protein is able to bind collagen and promote angiogenic network formation among vascular endothelial cells, indicating the regenerative potential of these ELMs
In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2
Get PDFBackground: Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches to accelerate development of reagents against infectious pathogens. Methods: Here, we developed an integrated approach combining synthetic, computational and structural methods with in vitro antibody selection and in vivo immunization to design, produce and validate nature-inspired nanoparticle-based reagents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Our approach resulted in two innovations: (i) a thermostable nasal vaccine called ADDoCoV, displaying multiple copies of a SARS-CoV-2 receptor binding motif derived epitope and (ii) a multivalent nanoparticle superbinder, called Gigabody, against SARS-CoV-2 including immune-evasive variants of concern (VOCs). In vitro generated neutralizing nanobodies and electron cryo-microscopy established authenticity and accessibility of epitopes displayed by ADDoCoV. Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Vaccinating mice resulted in antibodies cross-reacting with VOCs including Delta and Omicron. Conclusion: Our study elucidates Adenovirus-derived dodecamer (ADDomer)-based nanoparticles for use in active and passive immunization and provides a blueprint for crafting reagents to combat respiratory viral infections
Novel Sb−SnO2 Electrode with Ti3+ Self-Doped Urchin-Like Rutile TiO2 Nanoclusters as the Interlayer for the Effective Degradation of Dye Pollutants
Get PDFStable and efficient SnO2 electrodes are very promising for effectively degrading refractory organic pollutants in wastewater treatment. In this regard, we firstly prepared Ti3+ self-doped urchin-like rutile TiO2 nanoclusters (TiO2-xNCs) on a Ti mesh substrate by hydrothermal and electroreduction to serve as an interlayer for the deposition of Sb−SnO2. The TiO2-xNCs/Sb−SnO2 anode exhibited a high oxygen evolution potential (2.63 V vs. SCE) and strong ⋅OH generation ability for the enhanced amount of absorbed oxygen species. Thus, the degradation results demonstrated its good rhodamine B (RhB), methylene blue (MB), alizarin yellow R (AYR), and methyl orange (MO) removal performance, with the rate constant increased 5.0, 1.9, 1.9, and 4.7 times, respectively, compared to the control Sb−SnO2 electrode. RhB and AYR degradation mechanisms are also proposed based on the results of high-performance liquid chromatography coupled with mass spectrometry and quenching experiments. More importantly, this unique rutile interlayer prolonged the anode lifetime sixfold, given its good lattice match with SnO2 and the three-dimensional concave–convex structure. Consequently, this work paves a new way for designing the crystal form and structure of the interlayers to obtain efficient and stable SnO2 electrodes for addressing dye wastewater problems
Revealing the coaction of viscous and multistability hysteresis in an adhesive, nominally flat punch: a combined numerical and experimental study
Get PDFViscoelasticity is well known to cause significant hysteresis of crack closure and opening when an elastomer is brought in and out of contact with a flat, rigid, adhesive counterface. A separate origin of adhesive hysteresis is small-scale, elastic multistability. Here, we study a system in which both mechanisms act concurrently. Specifically, we compare the simulated and experimentally measured time evolution of the interfacial force and the real contact area between a soft elastomer and a rigid, flat punch, to which small-scale, single-sinusoidal roughness is added. To this end, we further the Green's function molecular dynamics method and extend recently developed imaging techniques to elucidate the rate- and preload-dependence of the pull-off process. Our results reveal that hysteresis is much enhanced when the saddle points of the topography come into contact, which, however, is impeded by viscoelastic forces and may require sufficiently large preloads. A similar coaction of viscous- and multistability effects is expected to occur in macroscopic polymer contacts and to be relevant, e.g., for pressure-sensitive adhesives and modern adhesive gripping devices
Adhesion of a cylindrical punch with elastic properties that vary radially
Get PDFThe adhesion of a rigid substrate and an adhered straight cylindrical punch with a non-homogeneous elastic modulus is analyzed. The stress distributions are obtained along the interface for various elastic modulus gradients. The calculations are performed in the commercial finite element software Abaqus using a user material (UMAT) subroutine to control the dependence of Young’s modulus on the radial position. The UMAT code is shared in the paper. The results reveal that the decreasing elastic modulus toward the perimeter of the punch can be used to significantly reduce the normal stress magnitudes in the singularity domain, which leads to stronger adhesion. The increase in the adhesion strength is characterized numerically. The effect of Poisson’s ratio is also analyzed
Cell-Derived Vesicles for Antibiotic Delivery—Understanding the Challenges of a Biogenic Carrier System
Get PDFRecently, extracellular vesicles (EVs) sparked substantial therapeutic interest, particularly due to their ability to mediate targeted transport between tissues and cells. Yet, EVs’ technological translation as therapeutics strongly depends on better biocompatibility assessments in more complex models and elementary in vitro–in vivo correlation, and comparison of mammalian versus bacterial vesicles. With this in mind, two new types of EVs derived from human B-lymphoid cells with low immunogenicity and from non-pathogenic myxobacteria SBSr073 are introduced here. A large-scale isolation protocol to reduce plastic waste and cultivation space toward sustainable EV research is established. The biocompatibility of mammalian and bacterial EVs is comprehensively evaluated using cytokine release and endotoxin assays in vitro, and an in vivo zebrafish larvae model is applied. A complex three-dimensional human cell culture model is used to understand the spatial distribution of vesicles in epithelial and immune cells and again used zebrafish larvae to study the biodistribution in vivo. Finally, vesicles are successfully loaded with the fluoroquinolone ciprofloxacin (CPX) and showed lower toxicity in zebrafish larvae than free CPX. The loaded vesicles are then tested effectively on enteropathogenic Shigella, whose infections are currently showing increasing resistance against available antibiotics
Breast Cancer Stem Cell-Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands
Get PDFThere are no targeted therapies for patients with triple-negative breast cancer (TNBC). TNBC is enriched in breast cancer stem cells (BCSC), which play a key role in metastasis, chemoresistance, relapse, and mortality. γδ T cells hold great potential in immunotherapy against cancer and might provide an approach to therapeutically target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor-sensing mechanisms, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. Herein, we show that patient-derived triple-negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T-cell immunotherapy. We unraveled concerted differentiation and immune escape mechanisms: xenografted BCSCs lost stemness, expression of γδ T-cell ligands, adhesion molecules, and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither promigratory engineered γδ T cells, nor anti–PD-1 checkpoint blockade, significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells and could be pharmacologically reverted by zoledronate or IFNα treatment. These results pave the way for novel combinatorial immunotherapies for TNBC
NERNST: a genetically-encoded ratiometric non-destructive sensing tool to estimate NADP(H) redox status in bacterial, plant and animal systems
Get PDFNADP(H) is a central metabolic hub providing reducing equivalents to multiple biosynthetic, regulatory and antioxidative pathways in all living organisms. While biosensors are available to determine NADP+ or NADPH levels in vivo, no probe exists to estimate the NADP(H) redox status, a determinant of the cell energy availability. We describe herein the design and characterization of a genetically-encoded ratiometric biosensor, termed NERNST, able to interact with NADP(H) and estimate ENADP(H). NERNST consists of a redox-sensitive green fluorescent protein (roGFP2) fused to an NADPH-thioredoxin reductase C module which selectively monitors NADP(H) redox states via oxido-reduction of the roGFP2 moiety. NERNST is functional in bacterial, plant and animal cells, and organelles such as chloroplasts and mitochondria. Using NERNST, we monitor NADP(H) dynamics during bacterial growth, environmental stresses in plants, metabolic challenges to mammalian cells, and wounding in zebrafish. NERNST estimates the NADP(H) redox poise in living organisms, with various potential applications in biochemical, biotechnological and biomedical research
Consolidation and performance gains in plasma-sintered printed nanoelectrodes
Get PDFWe report on the unusual, advantageous ageing of flexible transparent electrodes (FTEs) that were self-assembled from oleylamine-capped gold nanospheres (AuNPs) by direct nanoimprinting of inks with different particle concentrations (cAu = 3 mg mL−1 to 30 mg mL−1). The resulting lines were less than 2.5 μm wide and consisted of disordered particle assemblies. Small-Angle X-ray Scattering confirmed that particle packing did not change with ink concentration. Plasma sintering converted the printed structures into lines with a thin, electrically conductive metal shell and a less conductive hybrid core. We studied the opto-electronic performance directly after plasma sintering and after fourteen days of storage at 22 °C and 55% rH in the dark. The mean optical transmittance [T with combining macron]400–800 in the range from 400 nm to 800 nm increased by up to ≈ 3%, while the sheet resistance Rsh strongly decreased by up to ≈ 82% at all concentrations. We correlated the changes with morphological changes visible in scanning and transmission electron microscopy and identified two sequential ageing stages: (I) post-plasma relaxation effects in and consolidation of the shell, and (II) particle re-organization, de-mixing, coarsening, and densification of the core with plating of Au from the core onto the shell, followed by solid-state de-wetting (ink concentrations cAu < 15 mg mL−1) or stability (cAu ≥ 15 mg mL−1). The plating of Au from the hybrid core improved the FTEs' Figure of Merit FOM = [T with combining macron]400–800·Rsh−1 by up to ≈ 5.8 times and explains the stable value of ≈ 3.3%·Ωsq−1 reached after 7 days of ageing at cAu = 30 mg mL−1