Fecal Microbiota Transplantation: A Prospective Treatment for Type 2 Diabetes Mellitus.

Purpose of Review: The aim of this review is to summarize the role of gastrointestinal microbiome (GM) in the development of type 2 diabetes mellitus (T2DM). Besides, we discuss the feasibility of applying FMT in the treatment of T2DM and propose a series of processes to refine the use of FMT in the treatment of T2DM. Recent Findings: T2DM is a metabolic disease which is connected with the GM. According to many researches, GM can produce a variety of metabolites such as bile acid, short chain fatty acids, lipopolysaccharides and trimethylamine oxide which play an important role in metabolism. FMT is a method to regulate GM and has been observed to be effective in the treatment of metabolic diseases such as T2DM in some mouse models and people. However, there is still a lack of direct evidence for the use of FMT in the treatment of T2DM, and the process of FMT is not standardized. Summary: Dysregulation of GM is closely related to the development of T2DM. Promoting the conversion of GM in T2DM patients to normal population through FMT can reduce insulin resistance and lower their blood glucose level, which is an optional treatment for T2DM patients in the future. At present, the feasibility and limitations of applying FMT to the treatment of T2DM need to be further studied.

Ferroptosis: Mechanisms and role in diabetes mellitus and its complications.

Diabetes mellitus (DM) and its complications are major diseases that affect human health and pose a serious threat to global public health. Although the prevention and treatment of DM and its complications are constantly being revised, optimal treatment strategies remain unavailable. Further exploration of new anti-diabetic strategies is an arduous task. Revealing the pathological changes and molecular mechanisms of DM and its complications is the cornerstone for exploring new therapeutic strategies. Ferroptosis is a type of newly discovered iron-dependent regulated cell death. Notably, the role of ferroptosis in the occurrence, development, and pathogenesis of DM and its complications has gradually been revealed. Numerous studies have shown that ferroptosis plays an important role in the pathophysiology and pathogenesis of DM and its associated complications. The aim of this review is to discuss the known underlying mechanisms of ferroptosis, the relationship between ferroptosis and DM, and the relationship between ferroptosis as a mode of cell death and diabetic kidney disease, diabetic retinopathy, diabetic cardiomyopathy, diabetic osteoporosis, diabetes-associated cognitive dysfunction, DM-induced erectile dysfunction, and diabetic atherosclerosis.

Interleukin-4 Modulates Neuroinflammation by Inducing Phenotypic Transformation of Microglia Following Subarachnoid Hemorrhage.

Neuroinflammation, a key pathological feature following subarachnoid hemorrhage (SAH), can be therapeutically targeted by inhibiting microglia M1 polarization and promoting phenotypic transformation to M2 microglia. Interleukin-4 (IL-4) is a pleiotropic cytokine known to its regulation of physiological functions of the central nervous system (CNS) and mediate neuroinflammatory processes. However, its specific role in neuroinflammation and microglia responses following SAH remains unexplored. In this investigation, we established both in vivo and in vitro SAH models and employed a comprehensive array of assessments, including ELISA, neurofunctional profiling, immunofluorescence staining, qRT-PCR, determination of phagocytic capacity, and RNA-Seq analyses. The findings demonstrate an elevated expression of IL-4 within cerebrospinal fluid (CSF) subsequent to SAH. Furthermore, exogenous administration of IL-4 ameliorates post-SAH neurofunctional deficits, attenuates cellular apoptosis, fosters M2 microglia phenotype conversion, and mitigates neuroinflammatory responses. The RNA-Seq analysis signifies that IL-4 governs the modulation of neuroinflammation in microglia within an in vitro SAH model through intricate cascades of signaling pathways, encompassing interactions between cytokines and cytokine receptors. These discoveries not only augment comprehension of the neuropathogenesis associated with post-SAH neuroinflammation but also present novel therapeutic targets for the management thereof.

Space-Confined Synthesis of Monolayer Graphdiyne in MXene Interlayer.

Graphdiyne (GDY) is an artificial carbon allotrope that is conceptually similar to graphene but composed of sp- and sp2 -hybridized carbon atoms. Monolayer GDY (ML-GDY) is predicted to be an ideal 2D semiconductor material with a wide range of applications. However, its synthesis has posed a significant challenge, leading to difficulties in experimentally validating theoretical properties. Here, it is reported that in situ acetylenic homocoupling of hexaethynylbenzene within the sub-nanometer interlayer space of MXene can effectively prevent out-of-plane growth or vertical stacking of the material, resulting in ML-GDY with in-plane periodicity. The subsequent exfoliation process successfully yields free-standing GDY monolayers with micrometer-scale lateral dimensions. The fabrication of field-effect transistor on free-standing ML-GDY makes the first measurement of its electronic properties possible. The measured electrical conductivity (5.1 × 103 S m-1 ) and carrier mobility (231.4 cm2 V-1 s-1 ) at room temperature are remarkably higher than those of the previously reported multilayer GDY materials. The space-confined synthesis using layered crystals as templates provides a new strategy for preparing 2D materials with precisely controlled layer numbers and long-range structural order.

Discovery of CDK signature and CDK5 as potential biomarkers for predicting prognosis and immunotherapeutic response in gastric cancer peritoneal metastases.

Gastric cancer peritoneal metastases (GCPM) are a leading cause of death in gastric cancer patients. In this study, we focused on the expression of cyclin-dependent protein kinases (CDK), essential regulators of transcription, metabolism, and cell differentiation, in GCPM. Utilizing the GSE62254 cohort, we established a CDK signature (CDKS) model comprising ten CDK gene family members. Analysis of both the GSE62254 and TCGA cohorts revealed that patients with low CDKS had a worse prognosis compared to those with high CDKS. Furthermore, patients with high CDKS demonstrated positive responses from immunotherapy, as observed in the KIM cohort. We investigated the association between CDKS and the tumor microenvironment, including immune escape mechanisms. Immunohistochemistry analysis revealed a positive correlation between CDK5 and PD-L1 expression in gastric cancer. Furthermore, we found that CDK5 knockdown led to the inhibition of PD-L1 expression in gastric cancer cells. Our findings highlight the potential of CDKS as a prognostic biomarker and an indicator of immunotherapy response in gastric cancer patients. Moreover, our study suggests that targeting CDK5 could provide a new pathway for exploring immunotherapeutic research.

Biomarkers of obesity-mediated insulin resistance: focus on microRNAs.

Obesity and metabolic syndromes are becoming increasingly prevalent worldwide. Insulin resistance (IR) is a common complication of obesity. However, IR occurrence varies across individuals with obesity and may involve epigenetic factors. To rationalize the allocation of healthcare resources, biomarkers for the early risk stratification of individuals with obesity should be identified. MicroRNAs (miRNAs) are closely associated with metabolic diseases and involved in epigenetic regulation. In this review, we have summarized the changes in miRNA expression in the peripheral circulation and tissues of patients and animals with obesity-associated IR over the last 5 years and identified several candidate biomarkers that predict obesity-related IR. There are areas for improvement in existing studies. First, more than the predictive validity of a single biomarker is required, and a biomarker panel needs to be formed. Second, miRNAs are often studied in isolation and do not form a network of signaling pathways. We believe that early biomarkers can help clinicians accurately predict individuals prone to obesity-related IR at an early stage. Epigenetic regulation may be one of the underlying causes of different clinical outcomes in individuals with obesity. Future studies should focus on objectively reflecting the differences in miRNA profile expression in individuals with obesity-related IR, which may help identify more reliable biomarkers. Understanding the metabolic pathways of these miRNAs can help design new metabolic risk prevention and management strategies, and support the development of drugs to treat obesity and metabolic disorders.

Probiotics therapy show significant improvement in obesity and neurobehavioral disorders symptoms.

Obesity is a complex metabolic disease, with cognitive impairment being an essential complication. Gut microbiota differs markedly between individuals with and without obesity. The microbial-gut-brain axis is an important pathway through which metabolic factors, such as obesity, affect the brain. Probiotics have been shown to alleviate symptoms associated with obesity and neurobehavioral disorders. In this review, we evaluated previously published studies on the effectiveness of probiotic interventions in reducing cognitive impairment, depression, and anxiety associated with obesity or a high-fat diet. Most of the probiotics studied have beneficial health effects on obesity-induced cognitive impairment and anxiety. They positively affect immune regulation, the hypothalamic-pituitary-adrenal axis, hippocampal function, intestinal mucosa protection, and glucolipid metabolism regulation. Probiotics can influence changes in the composition of the gut microbiota and the ratio between various flora. However, probiotics should be used with caution, particularly in healthy individuals. Future research should further explore the mechanisms underlying the gut-brain axis, obesity, and cognitive function while overcoming the significant variation in study design and high risk of bias in the current evidence.

Inhibition of the pyroptosis-associated inflammasome pathway: The important potential mechanism of ginsenosides in ameliorating diabetes and its complications.

Diabetes mellitus (DM) and its complications have become an important global public health issue, affecting human health and negatively impacting life and lifespan. Pyroptosis is a recently discovered form of pro-inflammatory programmed cell death (PCD). To date, pyroptosis-associated inflammasome pathways have been identified primarily in the canonical and non-canonical inflammasome pathway, apoptotic caspase-mediated pathway, granzyme-mediated pathway, and streptococcal pyrogenic exotoxin B (SpeB)-mediated pathway. The activation of diabetes-mediated pyroptosis-associated factors play an important role in the pathophysiology of DM and its complications. Studies have shown that ginsenosides exert significant protective effects on DM and its complications. Through inhibiting the activation of pyroptosis-associated inflammasome pathways, and then the DM and its complications are improved. This review summarizes the subtypes of ginsenosides and their chemical characteristics, pharmacokinetics and side effects, the main pyroptosis-associated inflammasome pathways that have been discovered to date, and the potential mechanism of different subtypes of ginsenosides in the treatment of DM and its complications (such as diabetic cardiomyopathy, diabetic nephropathy, diabetic liver injury, diabetic retinopathy, and diabetic ischemic stroke) via anti-pyroptosis-associated inflammasome pathways. These findings may provide ideas for further research to explore ginsenoside mechanism in improving DM and its complications. However, many pyroptosis-associated inflammasome pathways and targets involved in the occurrence and development of DM and its complications are still unknown. In the future, further studies using in vitro cell models, in vivo animal models, and human disease models can be used to further elucidate the mechanism of ginsenosides in the treatment of DM and its complications.

Gut microbiota involved in spermatogenic function of Sancai Lianmei granules in obese mice.

Obesity is a well-established cause of reduced fertility and semen quality in men. Current evidence suggests that Sancai Lianmei granules (SCLM) effectively improve sexual function and semen quality in diabetic patients, while the gut microbiota can influence disease metabolism through various mechanisms. However, the effect of SCLM on the obesity-induced decrease in semen quality and on the gut microbiota is unclear. This study aimed to investigate the effects of SCLM on spermatogenic function and gut microbiota in obese mice. Obese mice were induced by a high-fat diet, and lipid metabolism, spermatogenic function, inflammatory factors, oxidative stress, and autophagy were analyzed to determine the effects of SCLM and SCLM-fecal microbiota transplantation (FMT). In addition, changes in the gut microbiota of mice were analyzed. SCLM and SCLM + FMT could effectively reduce the levels of total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL); decrease the expression of oxidative stress products malondialdehyde (MDA) and 8-hydroxyde-oxyguanosine (8-OHdG); and increase sperm density and sperm viability in obese mice while inhibiting the inflammatory responses and excessive cellular autophagy, indicating that SCLM and SCLM + FMT exerted a protective effect on spermatogenic functions. Furthermore, SCLM affected the gut microbiota composition in mice. This study determined that obesity can lead to reduced sperm motility and affect the composition of the gut microbiota, while SCLM can regulate blood lipids in mice directly or indirectly by regulating gut microbiota changes, and may improve sperm motility in obese mice by reducing oxidative stress and autophagy. In addition, FMT enhanced this effect, which may be related to the diversity of gut microbiota.

Administration of intramuscular AAV-BDNF and intranasal AAV-TrkB promotes neurological recovery via enhancing corticospinal synaptic connections in stroke rats.

Stroke causes long-term disability in survivors. BDNF/TrkB plays an important role in synaptic plasticity and synaptic transmission in the central nervous system (CNS), promoting neurological recovery. In this study, we performed non-invasive treatment methods focused on intramuscular injection into stroke-injured forelimb muscles, or intranasal administration using adeno-associated virus (AAV) vectors carrying genes encoding BDNF or TrkB. In a permanent rat middle cerebral artery occlusion (MCAO) model, we assessed the effects of combination therapy with AAV-BDNF and AAV-TrkB on motor functional recovery and synaptic plasticity of the corticospinal connections. Our results showed that BDNF or TrkB gene transduced in the spinal anterior horn neurons and cerebral cortical neurons. Compared to AAV vector treatment alone, behavioral and electrophysiological results showed that the combination therapy significantly improved upper limb motor functional recovery and neurotransmission efficiency after stroke. BDA tracing, immunofluorescence staining, qRT-PCR, and transmission electron microscopy of synaptic ultrastructure results revealed that the combination therapy not only potently increased the expression of Synapsin I, PSD-95, and GAP-43, but also promoted the axonal remodeling and restoration of abnormal synaptic structures. These findings provide a new strategy for enhancing neural plasticity and a potential means to treat stroke clinically.

Three-dimensional hierarchically porous MoS2 foam as high-rate and stable lithium-ion battery anode.

Architected materials that actively respond to external stimuli hold tantalizing prospects for applications in energy storage, wearable electronics, and bioengineering. Molybdenum disulfide, an excellent two-dimensional building block, is a promising candidate for lithium-ion battery anode. However, the stacked and brittle two-dimensional layered structure limits its rate capability and electrochemical stability. Here we report the dewetting-induced manufacturing of two-dimensional molybdenum disulfide nanosheets into a three-dimensional foam with a structural hierarchy across seven orders of magnitude. Our molybdenum disulfide foam provides an interpenetrating network for efficient charge transport, rapid ion diffusion, and mechanically resilient and chemically stable support for electrochemical reactions. These features induce a pseudocapacitive energy storage mechanism involving molybdenum redox reactions, confirmed by in-situ X-ray absorption near edge structure. The extraordinary electrochemical performance of molybdenum disulfide foam outperforms most reported molybdenum disulfide-based Lithium-ion battery anodes and state-of-the-art materials. This work opens promising inroads for various applications where special properties arise from hierarchical architecture.

Large-Area Flexible Memory Arrays of Oriented Molecular Ferroelectric Single Crystals with Nearly Saturated Polarization.

Molecular ferroelectrics (MFs) have been proven to demonstrate excellent properties even comparable to those of inorganic counterparts usually with heavy metals. However, the validation of their device applications is still at the infant stage. The polycrystalline feature of conventionally obtained MF films, the patterning challenges for microelectronics and the brittleness of crystalline films significantly hinder their development for organic integrated circuits, as well as emerging flexible electronics. Here, a large-area flexible memory array is demonstrated of oriented molecular ferroelectric single crystals (MFSCs) with nearly saturated polarization. Highly-uniform MFSC arrays are  prepared on large-scale substrates including Si wafers and flexible substrates using an asymmetric-wetting and microgroove-assisted coating (AWMAC) strategy. Resultant flexible memory arrays exhibit excellent nonvolatile memory properties with a low-operating voltage of <5 V, i.e., nearly saturated ferroelectric polarization (6.5 µC cm-2 ), and long bending endurance (>103 ) under various bending radii. These results may open an avenue for scalable flexible MF electronics with high performance.

Graphdiyne-Based Nanofilms for Compliant On-Skin Sensing.

Thin-film electronics pliably laminated onto the epidermis for noninvasive, specific, and multifunctional sensing are ideal wearable systems for health monitoring and information technologies. However, it remains a critical challenge to fabricate ultrathin and compliant skin-like sensors with high imperceptibility and sensitivities. Here we report a design of conductive hydrogen-substituted graphdiyne (HsGDY) nanofilms with conjugated porous structure and inherent softness for on-skin sensors that allow minimization of stress and discomfort with wear. Dominated by the subtle deformation-induced changes in the interdomain tunneling conductance, the engineered HsGDY sensors show continuous and accurate results. Real-time noninvasive spatial mapping of dynamic/static strains in both tensile/compressive directions monitors various body motions with high sensitivity (GF ∼22.6, under 2% strain), fast response (∼60 ms), and long-term durability (∼5000 cycles). Moreover, such devices can dynamically distinguish between the temperature difference and frequency of air inhaled and exhaled through the nostril, revealing a quantitative assessment of the movement/health of the human body. The proof-of-concept strategy provides an alternative route for the design of next-generation wearable organic bioelectronics with multiple electronic functionalities.

Fast water transport and molecular sieving through ultrathin ordered conjugated-polymer-framework membranes.

The development of membranes that block solutes while allowing rapid water transport is of great importance. The microstructure of the membrane needs to be rationally designed at the molecular level to achieve precise molecular sieving and high water flux simultaneously. We report the design and fabrication of ultrathin, ordered conjugated-polymer-framework (CPF) films with thicknesses down to 1 nm via chemical vapour deposition and their performance as separation membranes. Our CPF membranes inherently have regular rhombic sub-nanometre (10.3 × 3.7 Å) channels, unlike membranes made of carbon nanotubes or graphene, whose separation performance depends on the alignment or stacking of materials. The optimized membrane exhibited a high water/NaCl selectivity of ∼6,900 and water permeance of ∼112 mol m-2 h-1 bar-1, and salt rejection >99.5% in high-salinity mixed-ion separations driven by osmotic pressure. Molecular dynamics simulations revealed that water molecules quickly and collectively pass through the membrane by forming a continuous three-dimensional network within the hydrophobic channels. The advent of ordered CPF provides a route towards developing carbon-based membranes for precise molecular separation.

New Lead-free Organic-Inorganic Hybrid Semiconductor Single Crystals for a UV-Vis-NIR Broadband Photodetector.

Organic-inorganic hybrid semiconducting (OIHS) materials, which can detect broader spectral regions, are highly desired in several applications including biomedical imaging, night vision, and optical communications. Although lead (Pb)-halide perovskites have reached a mature research stage, high toxicity of Pb hinders their large-scale viability. Tin (Sn)-based perovskites are the most common OIHS broadband light absorbers that replace toxic Pb; however, they are extremely unstable due to the notorious Sn2+ oxidation. Herein, a novel, non-toxic, and solution-processed millimeter-sized OIHS single crystal [Ga(C3H7NO)6](I3)3 has been grown at room temperature. Both the absorption measurement and density functional theory calculations have confirmed a narrow indirect band gap of 1.32 eV. The corresponding photodetector based on this single crystal demonstrated excellent performance including an ultraviolet-visible-near infrared (UV-vis-NIR) response between 325 and 1064 nm, fast response time (trise/tdecay = 3.8 ms/5.4 ms), and profound air storage stability (41 h), thus outperforming most common photodetectors based on Sn-based perovskites. This work not only provides a profound understanding of this novel organic-inorganic single-crystal material but also demonstrates its great potential to realize the high-performance UV-vis-NIR broadband photodetectors.

Edaravone Dexborneol Treatment Attenuates Neuronal Apoptosis and Improves Neurological Function by Suppressing 4-HNE-Associated Oxidative Stress After Subarachnoid Hemorrhage.

Edaravone dexborneol is a novel neuroprotective drug that comprises edaravone and (+)-borneol in a 4:1 ratio. Phase II and III studies have demonstrated that Chinese patients treated with edaravone dexborneol within 48 h of AIS onset have better functional outcomes than those treated with edaravone alone. However, the effect of edaravone dexborneol on subarachnoid hemorrhage (SAH) has not yet been elucidated. This study aimed to investigate the therapeutic effects of edaravone dexborneol on SAH-induced brain injury and long-term behavioral deficits and to explore the possible mechanisms. The experimental rat SAH model was induced by an intraluminal puncture of the left middle cerebral artery (MCA). Edaravone dexborneol or edaravone at a clinical dose was infused into the tail vein for 3 days post-SAH surgery. Behavioral outcomes were assessed by a modified Garcia scoring system and rotarod, foot-fault, and corner tests. Immunofluorescence, Western blot, and ELISA methods were used to evaluate neuronal damage and oxidative stress. Our results showed that a post-SAH therapeutic regimen with edaravone dexborneol helped improve neurological function up to 21 days after SAH surgery and demonstrated a greater beneficial effect than edaravone alone, accompanied by an obvious inhibition of neuronal apoptosis in the CA1 hippocampus and basal cortex regions. Mechanistically, edaravone dexborneol not only suppressed the lipid peroxidation product malondialdehyde (MDA) but also improved the total antioxidant capability (TAC) 3 days after SAH. Notably, edaravone dexborneol treatment significantly inhibited the expression of another lipid peroxidation product, 4-hydroxynonenal (4-HNE), in the CA1 hippocampus and basal cortex, which are vital participants in the process of neuronal oxidative damage and death after SAH because of their acute cytotoxicity. Together, our results demonstrate that edaravone dexborneol confers neuroprotection and stabilizes long-term behavioral ability after SAH injury, possibly by suppressing 4-HNE-associated oxidative stress. These results may help develop new clinical strategies for SAH treatment.

Dewetting-Assisted Patterning of Organic Semiconductors for Micro-OLED Arrays with a Pixel Size of 1 µm.

The emergence of near-eye displays, such as head-mounted displays, is triggering a requirement for highly enhanced display resolution. High-resolution micro-displays with micro-organic light-emitting diodes (micro-OLEDs) can be a preferential candidate, owing to the mature industrialization of OLEDs along with the advantages of flexibility, light weight, and ease of processing. However, micro-OLEDs with pixel sizes down to micrometers are difficult to be achieved using conventional techniques such as fine metal mask evaporation and lithography. Here, a solution-processing approach to pattern organic semiconductors (OSCs) for micro-OLED arrays with the assistance of templated dewetting is demonstrated. Solvents containing organic functional materials are dewetted on the surface with hydrophobic/hydrophilic patterns to form ordered droplet arrays using dip-coating. Subsequently, patterned OSC films are produced by effectively controlling solvent evaporation. Micro-OLED arrays with a pixel size down to 1 µm are successfully fabricated by further deposition of emitting/electron transport layers and top electrodes. This approach can open an avenue for low-cost manufacturing of flexible and high-resolution micro-displays.

Ionic Functionalization of Multivariate Covalent Organic Frameworks to Achieve an Exceptionally High Iodine-Capture Capacity.

Adsorption-based iodine (I2 ) capture has great potential for the treatment of radioactive nuclear waste. In this study, we apply a "multivariate" synthetic strategy to construct ionic covalent organic frameworks (iCOFs) with a large surface area, high pore volume, and abundant binding sites for I2 capture. The optimized material iCOF-AB-50 exhibits a static I2 uptake capacity of 10.21 g g-1 at 75 °C and a dynamic uptake capacity of 2.79 g g-1 at ≈400 ppm I2 and 25 °C, far exceeding the performances of previously reported adsorbents under similar conditions. iCOF-AB-50 also exhibits fast adsorption kinetics, good moisture tolerance, and full reusability. The promoting effect of ionic groups on I2 adsorption has been elucidated by experimentally identifying the iodine species adsorbed at different sites and calculating their binding energies. This work demonstrates the essential role of balancing the textural properties and binding sites of the adsorbent in achieving a high I2 capture performance.

The "Dialogue" Between Central and Peripheral Immunity After Ischemic Stroke: Focus on Spleen.

The immune response generated by the body after the incidence of ischemic stroke, runs through the comprehensive process of aftermath. During this process of ischemic stroke, the central neuroinflammation and peripheral immune response seriously affect the prognosis of patients, which has been the focus of research in recent years. As this research scenario progressed, the "dialogue" between central nervous inflammation and peripheral immune response after ischemic stroke has become more closely related. It's worth noting that the spleen, as an important peripheral immune organ, plays a pivotal role in this dialogue. Multiple mechanisms have previously been reported for brain-spleen crosstalk after ischemic stroke. Further, neuroinflammation in the brain can affect the peripheral immune state by activating/inhibiting spleen function. However, the activation of the peripheral immune inflammatory response can work reversibly in the spleen. It further affects intracerebral neuroinflammation through the injured blood-brain barrier. Therefore, paying close attention to the role of spleen as the pivot between central and peripheral immunity in ischemic stroke may help to provide a new target for immune intervention in the treatment of ischemic stroke. In the present review, we reviewed the important role of spleen in central neuroinflammation and peripheral immune response after ischemic stroke. We summarized the relevant studies and reports on spleen as the target of immune intervention which can provide new ideas for the clinical treatment of ischemic stroke.

Mixed-dimensional MXene-hydrogel heterostructures for electronic skin sensors with ultrabroad working range.

Skin-mountable microelectronics are garnering substantial interest for various promising applications including human-machine interfaces, biointegrated devices, and personalized medicine. However, it remains a critical challenge to develop e-skins to mimic the human somatosensory system in full working range. Here, we present a multifunctional e-skin system with a heterostructured configuration that couples vinyl-hybrid-silica nanoparticle (VSNP)-modified polyacrylamide (PAM) hydrogel with two-dimensional (2D) MXene through nano-bridging layers of polypyrrole nanowires (PpyNWs) at the interfaces, featuring high toughness and low hysteresis, in tandem with controlled crack generation and distribution. The multidimensional configurations endow the e-skin with an extraordinary working range (2800%), ultrafast responsiveness (90 ms) and resilience (240 ms), good linearity (800%), tunable sensing mechanisms, and excellent reproducibility. In parallel, this e-skin platform is capable of detecting, quantifying, and remotely monitoring stretching motions in multiple dimensions, tactile pressure, proximity sensing, and variations in temperature and light, establishing a promising platform for next-generation smart flexible electronics.