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Ion interference including copper (Cu+)/calcium (Ca2+) overload activate cell‐specific death channels, damage mitochondria and disrupt cellular homeostasis, showing great potential in anti‐tumor therapy. However, the complex metabolic environment and the powerful self‐protection of tumors cause clinical failure of ion interference. Thus, metabolic disruption is expected an innovative strategy for the enhancement of ion interference. Herein, CuS‐α‐CHCA&penthiopyrad@CaCO3‐RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu+/Ca2+ dual‐overload anti‐tumor therapy assisted by metabolic‐symbiosis‐destruction strategy, realizing the collapse of tumor self‐protection. Specifically, precise CuS and CaCO3 delivery triggered irreversible Cu+/Ca2+ dual‐overload and reactive oxygen species (ROS) attack toward 4T1 cells. Meanwhile, α‐CHCA and penthiopyrad disturbed the metabolic symbiotic environment by disrupting the TCA cycle and preventing lactate efflux to aggravate intracellular acidosis and promote Fenton‐like reaction of Cu+, enhancing the sensitivity of tumor cells to copper death and Ca2+ overload. Further, aided by the metabolism of symbiosis, the destroyed tumor cells further activate the polarization of M1 macrophages and the maturation and antigen cross‐presentation of dendritic cells (DCs), which further eliminate tumor cells. In summary, an amplified anti‐tumor dual‐ion interference strategy assisted by metabolic symbiotic destruction is established, which is of great significance in improving the clinical effect of ion therapy for tumors. [ABSTRACT FROM AUTHOR]

Immune activation has been widely recognized to promote anti‐tumor effects in vivo. However, in previous anti‐tumor studies of combined photo/immunotherapy, the tumor apoptosis pathway is widely regarded as an independent process, which led to an incomplete understanding of the anti‐tumor mechanisms of the immune system during phototherapy. Herein, the decisive role of immune activation for the anti‐tumor effect of phototherapy and its specific mechanism, are investigated by preparing a melanin@chlorin e6@hyaluronic acid and oxidized Bletilla striata polysaccharide@NO‐donor (MCH‐OBN) nanoplatform, which integrated significant immune activation by phototherapy. The comparison of anti‐tumor effects between wild‐type mice and immunodeficient mice showed that effective phototherapy provided by the MCH‐OBN can not independently kill tumor cells in vivo, as it significantly depends on the immune activation. Furthermore, the activated immune system is demonstrated to destroy the tumor cell "barrier protection" by inhibiting the growth of cancer‐associated fibroblasts (CAFs), thereby ensuring the damage of heat, reactive oxygen species (ROS), and other components of phototherapy to the tumor. Thus, this work reveals for the first time the biological consequences of immune activation that determine the anti‐tumor effect of phototherapy by regulating CAF proliferation, which is of great significance for optimizing anti‐tumor clinical treatments through phototherapy. [ABSTRACT FROM AUTHOR]

The research on proximity sensing electronic skin has garnered significant attention. This electronic skin technology enables detection without physical contact and holds vast application prospects in areas such as human‐robot collaboration, human‐machine interfaces, and remote monitoring. Especially in the context of the spread of infectious diseases like COVID‐19, there is a pressing need for non‐contact detection to ensure safe and hygienic operations. This article comprehensively reviews the significant advancements in the field of proximity sensing electronic skin technology in recent years. It covers the principles, as well as single‐type proximity sensors with characteristics such as a large area, multifunctionality, strain, and self‐healing capabilities. Additionally, it delves into the research progress of dual‐type proximity sensors. Furthermore, the article places a special emphasis on the widespread applications of flexible proximity sensors in human‐robot collaboration, human‐machine interfaces, and remote monitoring, highlighting their importance and potential value across various domains. Finally, the paper provides insights into future advancements in flexible proximity sensor technology. [ABSTRACT FROM AUTHOR]

Implant‐associated complications arise due to non‐optimized cell–biomaterial interactions. It is well known that cells respond to their physicochemical microenvironment on 2D interfaces and 3D networks. Attempts to manipulate this interaction target surface parameters such as wettability (W), stiffness (S), and topography (T) to influence cell differentiation, adhesion, and morphology, due to induction of gene activation and protein expression. Investigating the combinatorial influence of all three mentioned parameters simultaneously remains challenging, though most realistic, since all three parameters are inherently present on a surface. Herein, a novel high‐throughput screening technology, which allows investigating the cell response of human bone‐marrow‐derived mesenchymal stem cells toward three varying biomaterial surface parameters simultaneously, is presented. The platform provides efficient screening and cell response readout to a vast amount of combined biomaterial surface properties, in a single‐cell experiment. Surface gradients of aligned wrinkle T, S, and W are orthogonally combined giving four combinatorial surfaces. The screening outcome is validated by translating interesting regions to homogeneous surfaces. Cells are found to behave similar to the screening in terms of adhesion, spreading, and vimentin expression. The technology tremendously supports the identification of optimal surface parameter combinations and potentially addressing many of the current implant‐associated complications. [ABSTRACT FROM AUTHOR]

When skin trauma occurs, rapid achievement of the post‐wound closure is required to prevent microbial invasion, inhibit scar formation and promote wound healing. To develop a wound dressing for accelerating post‐wound‐closure and wound healing, a thermo‐responsive and tissue‐adhesive hydrogel with interpenetrating polymer networks (IPN) is fabricated based on N‐dimethylbisacrylamide (NIPAM) and glutaraldehyde (GTA) cross‐linked hyaluronic acid (HA). Results not only confirm the thermo‐stimulated self‐contraction and tissue adhesiveness of the HA‐based IPN (PNI‐HA), which effectively aids wound closure via mechanical stretch, but also verify the hemocompatibility and cytocompatibility of PNI‐HA that tend to accelerate wound healing. In vivo, a mouse model of total skin defect demonstrates that PNI‐HA acting as hydrogel sealant significantly achieves the sutureless post‐wound‐closure at the early stage of wound healing, and then promotes wound healing by reducing inflammatory cells infiltration, promoting angiogenesis as well as reducing collagen deposition. These results indicate that the developed thermo‐responsive and tissue‐adhesive hydrogel dressing offers a candidate to serve as a tissue sealant for wound healing. [ABSTRACT FROM AUTHOR]

Developing bio‐multifunctional patches with natural extracellular matrix‐like structures, excellent high adhesion in the wet state, self‐healing ability, antibacterial activity, and favorable cell responses for accelerating tissue healing is highly desirable in clinical applications. Herein, bio‐multifunctional composite hydrogels are developed by coupling carboxymethyl chitosan and 4‐arm poly (ethylene glycol) aldehyde for full‐thickness abdominal wall defect repair. The prepared hydrogels exhibit excellent self‐healing and mechanical properties, high adhesion in the wet state, and significant antibacterial ability. In vitro cellular experiments show that the hydrogels combined with recombinant bovine basic fibroblast growth factor remarkably promote cell proliferation and then accelerate full‐thickness abdominal wall defect repair in a rat model. The histomorphological evaluation shows that compared to the commercial polypropylene mesh used clinically, the designed hydrogel patches facilitate an increase in the thickness and integrity of the abdominal wall tissue by upregulating the production of Ki67, enhancing the formation of collagen, inducing neovascularization, and inhibiting inflammation by reducing the expression of IL‐6, TNF‐α, and IL‐1β. The results demonstrate that this novel bio‐multifunctional hydrogel patch holds great potential for the treatment of full‐thickness abdominal wall defects. [ABSTRACT FROM AUTHOR]

Although electrospun polymer fibers with unique (bio)physicochemical features have been demonstrated to regulate cellular phenotype, their specific effect on organelles has not been examined closely. Herein, this work investigates the impact of aligned electrospun poly(L‐lactic acid) (PLLA)/graphene (Gr) microfibers with the nanoporous surface on the mitochondrial responses of human aorta smooth muscle cells. Highly aligned PLLA/Gr microfibers with an average fiber diameter of ≈1.3 µm are prepared via a novel stable jet electrospinning strategy. Nanoporous topography is formed onto individual fiber surfaces using highly volatile solvent dichloromethane and suitable ambient humidity. Further, it is found that the addition of Gr in PLLA fibers significantly facilitates the formation of mitochondrial reactive oxygen species (mROS) and adenosine triphosphate (ATP) as well as mitochondrial autophagy and division by upregulating the protein expression of microtubule‐associated protein light chain 3, mitochondrial fission 1 protein, and dynamin‐related protein 1. In contrast, the introduction of the nanoporous structure greatly inhibits the generation of mROS and ATP as well as mitochondrial autophagy and division. The work thus indicates that the incorporation of nanotopography and Gr in/on the PLLA fibers can offer additional physicochemical stimuli to regulate the mitochondrial responses of cells. [ABSTRACT FROM AUTHOR]

The interface between materials and cells plays a critical role in many biomedical applications. Inspired by the hierarchical architecture of collagen, most abundant structure in the extracellular matrix (ECM), a multiscale hierarchical topography is designed to mimic the collagen nano/micro hierarchical topography. It is hypothesized that the ECM topography affects osteogenesis of human mesenchymal stem cells but until now, it cannot be studied without the biochemical and mechanical influences of the ECM. The multiscale hierarchical topography is achieved by innovatively using sequentially aligned topography preparation via a silicone stretch‐oxidation‐release method and imprinting lithography. The anisotropically hierarchical topography influences stem cell morphology, orientation, and osteogenic differentiation. Intriguingly, the design resembling that of assembled collagen, exhibits the highest degree of osteogenesis. The hierarchical topotaxis effects are further exemplified by the enhanced vinculin expression, cell contractility, and more pronounced nuclear translocation of Yes‐associated protein with the collagen‐mimicking topography, indicative for enhanced osteogenesis. The developed multiscale hierarchical system provides insights into the importance of specific biological ECM‐like topography by decoupling the biochemical influence. Various diseases, cancer, osteoarthritis, and fibrosis display impaired ECM structures, and therefore this system may have a great potential for tissue engineering approaches and developing in vitro disease models. [ABSTRACT FROM AUTHOR]

The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72‐specific pathology and TDP‐43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly‐GA promoted cytoplasmic mislocalization and aggregation of TDP‐43 non‐cell‐autonomously, and anti‐GA antibodies ameliorated TDP‐43 mislocalization in both donor and receiver cells. Cell‐to‐cell transmission of poly‐GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP‐43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly‐GA‐dependent mislocalization of TDP‐43. Boosting proteasome function with rolipram reduced both poly‐GA and TDP‐43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly‐GA promotes TDP‐43 aggregation by inhibiting the proteasome cell‐autonomously and non‐cell‐autonomously, which can be prevented by inhibiting poly‐GA transmission with antibodies or boosting proteasome activity with rolipram. Synopsis: Poly‐GA promotes cytoplasmic mislocalization and aggregation of TDP‐43 via non‐cell‐autonomous proteasome inhibition and ubiquitination within the nuclear localization signal. Proteasome activation and poly‐GA antibodies ameliorate TDP‐43 pathology. Poly‐GA promotes TDP‐43 aggregation by proteasome inhibition even upon cell‐to‐cell transmission.Anti‐GA antibodies reduce TDP‐43 mislocalization.Ubiquitination within the NLS inhibits nuclear import of TDP‐43.Proteasome activation with rolipram ameliorates poly‐GA and TDP‐43 pathology. [ABSTRACT FROM AUTHOR]

Abstract: Controlling cell organization is still a major bottleneck in biointerface engineering when the material dimensions decrease to the nanoscale. Here, Au nanowire‐patterned array platforms with multiscale design from the macroscale to the nanoscale are developed for studying human bone marrow–derived mesenchymal stem cell (hBM‐MSC) response. When the angle of the Au nanowires on glass is increased from 0° to 90°, hBM‐MSC arrangement exhibits a transition from a unidirectional distribution induced by a vector response to a bimodal polarization pattern. The degree of cell vector response and elongation decreases with increasing nanowire angles from 0° to 90°. Further, it is demonstrated that the specific cell adhesion and organization are dependent on the surface micro/nanotopography, which is greatly enhanced by introducing stem cell‐material affinity differences. An ideal model and new insights into a deeper understanding of cell–nano‐biointerface interactions are provided. [ABSTRACT FROM AUTHOR]

Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat ( DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis ( ALS) and frontotemporal lobar degeneration ( FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non- ATG ( RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly- GA, poly- GP, and poly- PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly- GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly- GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80. Treatment with anti- GA antibodies inhibits intracellular poly- GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly- GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/ FTD. [ABSTRACT FROM AUTHOR]

The article discusses tailoring cell-surface interactions involved in designing and developing medical implants and scaffold materials required for regenerative medicine and tissue engineering. Particular focus is given to the mechanical properties of nanotopologies in polydimethylsiloxane. Translating hard nanotopology into soft polymeric hydrogel structures via hydrogel imprinting lithography is also discussed.

Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration ( FTLD) and amyotrophic lateral sclerosis ( ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins ( DPR). Repeat-dependent toxicity may affect nuclear import. hn RNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA. We now report that a reduction of nuclear hn RNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hn RNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hn RNPA3. Reduced nuclear hn RNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hn RNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci. [ABSTRACT FROM AUTHOR]

Abstract: Two‐parameter contributions of stiffness and wettability display altered behavior of hBM‐MSCs as compared to solely investigating the wettability of the biointerface with a homogenous stiffness. The importance of double parameter influence is identified by using newly developed double linear wettability–stiffness gradients. The interfaces show that substrate stiffness can influence cell adhesion and spreading both positively and negatively in combination with wettability. This effect is validated by decoupling the stiffness gradient using a wettability gradient composed of a monolayer on glass ensuring a homogenous stiffness. [ABSTRACT FROM AUTHOR]

Severe resistance of doxorubicin (DOX) caused by drug efflux and immunosuppression has led to a high treatment failure risk of breast cancer (BC). Compared with the single atom nanozymes, the bi‐single‐atomic nanozymes obtained through sequential single‐atom synthesis strategy in different spaces of the same nanomaterial, can significantly improve the space utilization efficiency and catalytic capacity. In this study, bi‐single‐atom nanozymes (Zn/Cu‐BSAN‐DOX NPs) are designed to reverse BC DOX resistance by causing damage to mitochondria of mesenchymal stem cells (MSCs) and 4T1 cells through reactive oxygen species (ROS) amplification. In situ H2O2 self‐supply is improved by releasing DOX through activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). ROS amplification is triggered by enhanced chemodynamic therapy (CDT) and sonodynamic therapy (SDT) of Zn/Cu‐BSAN, which efficiently reverses the DOX resistance by breaking the hyaluronic acid (HA) barrier and DOX efflux. Furthermore, ROS amplification significantly promotes the immune improvement including DCs maturation, T cell activation, and the polarization of M1 macrophage. In summary, as “hexagonal” anti‐tumor warrior, Zn/Cu‐BSAN‐DOX NPs show great potential for multimodal DOX‐resistant BC therapy, which further expands the new preparation strategy and the clinical anti‐tumor application paradigm of single‐atom nanozymes. [ABSTRACT FROM AUTHOR]

Pathological scars (PS) are involved in the excessive response of inflammation and overactivation of myofibroblasts. Herein, a novel microneedle (MN) patch based on the adipose‐derived stem cell concentrated conditioned medium (ADSCC‐CM) cross‐linked keratin hydrogel is developed to load triamcinolone acetonide (TA), thereby achieving the dual‐drug delivery of ADSCC‐CM and TA to simultaneously reduce the inflammation and guide myofibroblast behaviors. Results not only confirm the ability of ADSCC‐CM to drive the formation of keratin‐based hydrogel, but also verify the dual‐drug release capacities of the hydrogel‐developed MNs (TA@AC‐MN). Using human hyperplastic scar fibroblast (HSF), the combination of ADSCC‐CM and TA demonstrates a pronounced synergistic effect in mitigating the detrimental effects of the inflammatory microenvironment on HSFs, including suppressing the production of reactive oxygen species and attenuating the expression of inflammatory factors. Compared with the clinically used TA, TA@AC‐MN promotes scar biomimetic repair (i.e., optimizing the proportion of collagen and increasing the tissue tensile strength). This study demonstrates that TA@AC‐MN has the capacity to provide a self‐managing and minimally invasive therapeutic strategy for PS. [ABSTRACT FROM AUTHOR]

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non‐canonical translation of the expanded repeat results in abundant poly‐GA inclusion pathology throughout the CNS. (GA)149‐CFP expression in mice triggers motor deficits and neuroinflammation. Since poly‐GA is transmitted between cells, we investigated the therapeutic potential of anti‐GA antibodies by vaccinating (GA)149‐CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin‐(GA)10 conjugates and pre‐aggregated carrier‐free (GA)15. Only ovalbumin‐(GA)10 immunization induced a strong anti‐GA response. The resulting antisera detected poly‐GA aggregates in cell culture and patient tissue. Ovalbumin‐(GA)10 immunization largely rescued the motor function in (GA)149‐CFP transgenic mice and reduced poly‐GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin‐(GA)10‐immunized poly‐GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP‐43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers. Synopsis: The study proposes active immunization targeting poly‐GA as a prevention approach for pre‐symptomatic C9orf72 mutation carriers at risk of developping ALS/FTD. Immunization using Ovalbumin‐(GA)10 largely rescued motor deficits in a poly‐GA mouse model. Ovalbumin‐(GA)10 immunization drives strong anti‐GA response without apparent side effects.Ovalbumin‐(GA)10 immunization reduces motor deficits and poly‐GA inclusions.Ovalbumin‐(GA)10 immunization attenuates neuroinflammation, neuroaxonal damage and reduces cytoplasmic TDP‐43 mislocalization. [ABSTRACT FROM AUTHOR]

New high‐throughput technologies for cell–material interaction studies provide researchers with powerful tools to speed up research in the field of biomaterial–cell interactions. However, sharing technologies is often difficult due to the necessity of specific knowledge and experiences. Engineered surfaces can elucidate effects of surface topography on cell behavior, which is of critical value for gaining control over cellular processes. Here, the translation of a gradient‐based high‐throughput cell screening approach for aligned nano/micro topographies interacting with cells is presented. An aligned topography 96‐well plate is created by upscaling of highly specific gradient technology. The resulting cell culture dishes are compatible with general laboratory and imaging equipment, and the platform allows for studying cell behavior with regard to adhesion and alignment. The challenge lies in increasing the dimensions of the previous 1 × 1 cm gradient topography substrate, to be able to cover the span of a 96‐well plate and translate it into a standardized cell‐screening tool. Adhesion experiments of human bone marrow derived mesenchymal stem cells confirm the standardization, compatibility, and usability of the technology. In the process of using multi‐system imaging and analysis, it becomes apparent that future challenges need to include universally applied data analysis approaches. [ABSTRACT FROM AUTHOR]

A novel design of absorptive frequency selective surface (AFSS) with tunable absorptive/switchable transmissive property is presented. The AFSS is comprised of a resistive surface and a metallic bandpass FSS on which PIN diodes are mounted. By changing the working state of the PIN diode, a tunable absorption performance at 3.5–11.2 GHz is achieved with a switchable transmission at the frequency of 0.83 GHz. A prototype of the proposed structure is fabricated and measured under the normal incidence. [ABSTRACT FROM AUTHOR]

Surface gradients provide a powerful platform to accelerate multiscale design by efficiently studying of material–cell interactions to ultimately enhance function of synthetic clinical biomaterials. Herein, a novel orthogonal double gradient is reported in which surface stiffness and wettability vary independently and continuously in perpendicular directions, providing unique combinations of stiffness and wettability over a broad range (stiffness: 6–89 MPa; water contact angle: 29°–90°). It is found that mesenchymal stem cell behavior is nonlinearly regulated by surface stiffness and wettability. These combined stiffness and wettability properties of a material significantly affect stem cell adhesion, spreading, nucleus size, and vinculin expression. This high‐throughput screening system enables elucidation of the relationships between biointerface properties and biological behavior, and thereby serves a potential tool for accelerating the development of high‐performance biomaterials. Orthogonal stiffness and wettability gradients within a single substrate are developed for elucidating combined physical parameter influences on stem cell behavior and thereby gaining insights in desired cellular responses. Cell behavior is nonlinearly regulated by surface stiffness and wettability. The optimal combined properties for promoting cell adhesion, nucleus size, and vinculin expression are identified based on the orthogonal double gradients. [ABSTRACT FROM AUTHOR]