Saikosaponin b1 (Ssb1), a natural oleanane-type triterpenoid saponin, exhibits antifibrosis activity by inhibiting the activation of hepatic stellate cells (HSCs), but the specific underlying molecular mechanisms are unknown. Here, it is found that Ssb1 could directly bind with the signal transducer and activator of transcription 3 (STAT3) and effectively inhibit the activation of HSCs. Proteomic techniques and molecular simulation revealed that Ssb1 is mainly bound to the S319 residues of STAT3 in the coiled-coil domain. Further studies indicated that Ssb1 binding with STAT3 inhibited its transcriptional activity, and regulated glioma-associated oncogene-1 (Gli1) expression in the Hedgehog signaling pathway. Besides, Ssb1 binding blocked interaction between STAT3 and Gli1, which promoted degradation of Gli1 protein by suppressor of fused homolog (SUFU) and the ubiquitin-proteasome system. The loss function of Gli1 led to decreased expression of Bcl2 and promoted the apoptosis of activated HSCs. Moreover, STAT3 ablation abolished the Ssb1-mediated antifibrotic effects. These findings show that STAT3 plays a vital role in Ssb1 treatment of liver fibrosis, and Ssb1 as a STAT3 inhibitor might be a promising therapeutic candidate for the treatment of hepatic fibrosis.

Irregular dendrite growth and complex side reactions pose critical challenges that significantly impede the further industrialization of aqueous zinc-ion batteries (AZIBs). The “competitive co-solvents” strategy could introduce hydrogen bond (H-bond) accepting sites to effectively alleviate the free water molecules. however, it suffers from low conductivity, high cost, and safety risks. Herein, we selected N, N'-methylenebisacrylamide (MBA) as a trace additive with amide groups to decrease the activity of water by disrupting the H-bond. The MBA additive, which incorporates both hydrogen bond donor and acceptor functionalities, successfully restricts H₂O molecules within a double-site anchoring configuration. This configuration enhances hydrogen-bonding interactions and breaks part of the original hydrogen bond network among H₂O molecules, thereby significantly restraining parasitic side reactions due to the decomposition of active water. Additionally, MBA molecules adsorbed on the surface of the Zn anode could regulate the desolvation and nucleation processes of zinc ions, achieving dense and flat zinc deposition. A high Zn reversibility with Coulombic efficiency (CE) of 99.74% and ultra-long lifespan of 2800 cycles at 1 and 0.5 mAh cm⁻² was demonstrated. Besides, a highly reversible Zn electrode significantly boosted the overall performance of Zn//Zn symmetric cells of 1500 h at 5 mA cm⁻² and Zn//V₂O₅ full cell of 2000 cycles at 5 A g⁻¹.

The immune characteristics and pathological mechanisms of COVID-19 and tuberculosis coinfection are not well understood. Single-cell RNA sequencing has emerged as a powerful tool for dissecting complex immune responses and cellular interactions in infectious diseases. Here, we employed scRNA-seq, combined with laboratory examinations and clinical observations, to elucidate potential mechanisms of immunopathology and protective immunity in coinfected patients. Substantial alterations in immune cell populations in patients with severe coinfection were observed, characterized by severe lymphopenia and massive expansion of myeloid cells. Lymphocytopenia may have resulted from lymphocyte apoptosis and migration. Systemic upregulation of S100 family proteins, mainly released by classical monocytes, might contribute to inflammatory cytokine storm via S100-TLR4-MyD88 signaling pathway in severely coinfected patients. Myeloid cells may contribute to immune paralysis in severe cases through expansion of myeloid-derived suppressor cells and dysregulated dendritic cell function. The immune landscape of T cells in severe patients were featured by dysregulated Th1 response, widespread exhaustion and increased cytotoxic, apoptosis, migration and inflammatory states. We observed increased plasma cells and overexpression of B-cell-activation-related pathways in severe patients. Together, we provide a comprehensive atlas illustrating the immune response to coinfected patients at the single-cell resolution and highlight mechanisms of pathogenesis in severe patients.

Electrochemical CO₂ electrolyzers are increasingly recognized for their potential to convert CO₂ into valuable chemical feedstocks, addressing critical environmental and economic challenges. Traditionally, the catalytic properties of the cathode, where CO₂RR directly occurs, have been the main focus of research due to their control over product selectivity. More recently, however, membrane-based electrolyzers—commonly used in fuel cells and water electrolyzers—have shown substantial potential for commercial CO₂ reduction, offering improved scalability and efficiency. Nevertheless, the complex components in membrane-based electrolyzers require precise optimization, as each unit directly impacts system performance and product selectivity. In this review, the structures and components of membrane-based CO₂ electrolyzers are systematically examined, including the electrolyzer design, flow channels, membranes, electrolytes, CO₂ supply units, and electrodes. Recent innovations in the optimization of these components are highlighted to provide insights into advancing CO₂RR technology toward commercially feasible applications. This approach can assist considerably in improving the CO₂RR electrolyzer performance, thereby helping predict optimal pathways for commercial realization and guide future development.

Multidrug-resistant Klebsiella pneumoniae constitutes a significant threat as a nosocomial pathogen, and no licensed vaccines are currently available. Generalized modules for membrane antigens (GMMA) have recently been recognized as a promising platform for developing outer membrane vesicle (OMV) vaccines against numerous infectious diseases. The study was carried out in use of the W3110 ΔwbbH-L ΔlpxM::lpxE in which E. coli was treated in order to eliminate the endogenous polysaccharide and use two new ones (polysaccharides from Klebsiella). The exogenous polysaccharides were accurately displayed on the surface of spontaneously released OMVs. The immune responses evoked by subcutaneous administration of these vaccines were evaluated, and the protective effects were assessed using a mouse intraperitoneal challenge model. Interference in the biosynthesis of endogenous polysaccharides (such as deleting related gene clusters) is a viable approach to increasing the yield of glycoengineered GMMA vaccines (geGMMA). The geGMMA platform, which is conducive to safer large-scale production, lays the foundations for the development of GMMA vaccines decorated with exogenous glycan antigens derived from pathogenic bacteria.

The inhibition of joint synovial inflammation, caused by poor oxygen (O₂) supply and excessive reactive oxygen species (ROS) generation, is an important treatment strategy for rheumatoid arthritis (RA). Herein, we formulated a targeted ruthenium-based anti-inflammatory nanosystem consisting of ruthenium clusters-loaded F127-organosilica micelles with folic acid (FA) modification (RuFOMs-FA) for RA treatment through a two-stage macrophage regulatory mechanism. At the first stage, RuFOMs-FA exhibited excellent photothermal capability with a high photothermal conversion efficiency of 55.3% upon external-field 808 nm NIR irradiation, which further induced the death of M1 macrophages through the folic acid-mediated active targeting pathway. Further, the resultant nanoagent mimicked enzymes displayed catalase-like and superoxide dismutase-like activities for endogenously scavenging ROS and producing O₂ to induce the polarization of pro-inflammatory M1 to anti-inflammatory M2 macrophages in the RA physiological environment. More importantly, RuFOMs-FA effectively alleviated hypoxia, inflammation, and cartilage destruction in the synovial joints in a rat RA model by the two-stage macrophage regulatory mechanism. Consequently, it is highly expected that the developed RuFOMs-FA could be applied as a new noble metal-based anti-inflammatory candidate nanosystem for efficient and safe RA treatment.

Photodynamic therapy (PDT) triggers immunogenic cell death (ICD) within the tumor microenvironment, consequently enhancing tumor immunotherapy. However, the maximum absorption wavelengths of first and second-generation PDT photosensitizers limit the penetration depth of therapeutics, resulting in insufficient anti-tumor outcomes. This study reports a custom-designed polymer, PTSQ, which exhibits significant absorption in the near-infrared region (NIR) window and fluorescence emission spectra within the NIR II range, demonstrating excellent PDT efficiency. Additionally, PTSQ self-assembles into nanomicelles, exhibiting outstanding siRNA delivery. To further enhance tumor immunotherapy, we introduce an immune checkpoint blockade strategy and prepared PTSQ/siPD-L1 complexes. We present a novel approach to tumor treatment by combining NIR light-activated PDT and ICD to enhance siPD-L1 therapy. At the cellular level, PTSQ/siPD-L1 complexes exhibit potent induction of ICD while concurrently suppressing PD-L1 gene expression. In vivo, these complexes significantly impede the growth of CT26, 4T1, and patient-derived xenograft (PDX) tumors. This effect is achieved by promoting in situ ICD, which reverses tumor environment and activates immune cells in tumors and spleens, including T cells, dendritic cells (DCs), and macrophages. Overall, this study offers insights for the development of NIR II-guided cancer immunotherapy and underscores the efficacy of PDT in conjunction with checkpoint blockade for cancer treatment.

Metal surface coating modification is an effective method to solve the problem of corrosion and inflammation in biometal clinical applications. Hydrogel is currently a commonly used biometal surface coating material. Because of its hydrophilicity, biocompatibility, and good biomechanical properties, hydrogel is widely used in clinical applications. Functionalized hydrogel coatings on biometal surfaces can effectively ameliorate problems such as corrosion, late thrombosis, inflammation, and other complications of implanted metals. Therefore, realizing a strong bond between biometal and hydrogel is a hot issue. This article centers on the bonding of hydrogel to biometal, focusing on a review of (i) biometal surface pretreatment methods, (ii) biometal-hydrogel bonding methods, and (iii) application of hydrogel coatings on biometal surfaces.

Although iodine (I) doped Li₆PS₅Cl argyrodite sulfide electrolytes have attracted significant attention, a comprehensive understanding of how I⁻ occupancy influences ionic conductivity is still lacking. Herein, through ab initio molecular dynamics theoretical calculations, it was revealed that the incorporation of excess halogen at the sulfur site (4d) significantly accelerates the inter-cage jumps of Li⁺ with a low migration energy barrier of 0.28 eV, enhancing the ionic diffusion kinetics. Subsequently, iodine-rich Li_6−xPS_5−xClI_x (0 ≤ x ≤ 0.2) electrolytes are successfully synthesized and deliver high ionic conductivity. Moreover, a stable Li/Li_6−xPS_5−xClI_x interface is achieved to inhibit side reactions and lithium dendrite growth. Therefore, Li symmetric cells with the optimized electrolyte present splendid cyclic stability (7000 h at 0.1 mAh cm⁻² and 1500 h at 0.5 mAh cm⁻²). The constructed full cells with optimized electrolytes exhibit excellent electrochemical properties at a broad temperature range and with different active materials. This work deepens the understanding of the relationship between ion transport and structure in lithium argyrodite sulfide electrolytes.

Autophagy is a process of engulfing cytoplasmic proteins or organelles, thereby fulfilling cells’ metabolic needs and the renewal of specific organelles. Given its key roles in tumor progression, autophagy has attracted tremendous attention in cancer therapies. Notably, there is a megatrend to integrating autophagy regulation into mainstream treatments. This review focuses on autophagy-targeting nanomedicine (ApT-NM) to modulate autophagy in tumor therapy, including the unmodified and functionalized nanoparticles that target tumors by carrying autophagy modulators. On the one hand, it can reverse treatment resistance by inhibiting protective autophagy, and on the other hand, it can promote the death of cancer cells through type II apoptosis by inducing autophagy. Moreover, advanced nanoplatforms combining various treatments (such as chemotherapy, radiotherapy, photothermal therapy, and photodynamic therapy, etc.) have also been summarized. Last, the future perspectives and directions for ApT-NM research are provided, hoping to emphasize this rising filed and promote the development of ApT-NM.

Type 2 diabetes (T2D) is a prevalent metabolic disease inducing alterations of multiple organ systems with currently no cure. Extracellular vesicles (EVs) have been increasingly noticed as one critical paracrine communicator inducing insulin resistance and metabolic disorders in T2D, but clinically available pharmaceuticals for controlling pathological EV release is lacking. Here, we discover that the natural monosaccharide D-mannose exists with an altered level in the db/db mouse T2D model. Intriguingly, oral administration of D-mannose with the drinking water safely ameliorates diabetic symptoms in db/db mice. D-mannose administration does not critically regulate the gut microbiome and circulatory T lymphocytes in treating T2D, while administrated D-mannose rapidly accumulates in the liver, alleviates hepatic steatosis and rescues insulin resistance. Regarding the mechanism, the T2D pathological EVs released by macrophages are targeted and reduced by D-mannose, which metabolically inhibits CD36 expression and restores function of hepatocytes. Importantly, by regulating macrophage EV release, D-mannose administration reveals extra-hepatic benefits and retards diabetic bone loss. Taken together, our findings unveil D-mannose as a candidate T2D therapeutic and highlight sugars governing intercellular EV crosstalk, paving an avenue for pharmaceutical T2D approaches with amelioration of multi-organ deteriorations.

Droplet boiling is a common occurrence in many industrial processes, but it can be hindered by the Leidenfrost effect. The Leidenfrost point (LP), defined as the temperature at which an accumulated and stagnant vapor forms between the liquid and the heated solid, consequently deteriorates cooling performance. In this study, inspired by nature, we demonstrate how using a nano-micro hierarchical triple-passage architecture with a higher aspect ratio enhances both vapor and liquid spreading dynamics, boosts heat transfer, and thus elevates the LP. Our results show that the LP is promoted to 273°C, which is a delay of approximately 130°C compared to the LP of 145°C on a copper surface. Through theoretical analysis, we develop a multi-force competition model to reveal the underlying physics of this sustained nucleate boiling. Our findings challenge traditional wisdom, indicating that lower impact velocities of a droplet, though sacrificing the convection, delay the LP through impact pattern manipulation. Additionally, we adopt a physics-informed deep neural network framework to accurately model the nonlinear behavior of droplet boiling (from nucleate boiling to LP) on various surfaces within an ≈11% error. The results here have potential applications in designing more efficient droplet-based boiling heat transfer devices and in controlling droplet boiling at high temperatures.

Zinc hybrid ion batteries (ZHIBs) represent an innovative alternative building upon the strengths of zinc-ion batteries (ZIBs) while overcoming their inherent challenges. ZHIBs employ a versatile strategy of utilizing monovalent ions as charge carriers, which not only accelerates the diffusion kinetics but also fortifies the structural integrity of the cathode materials. This approach effectively addresses the issues of slow divalent zinc ion migration and the strong coulombic interactions that have been noted in ZIBs. Prussian blue analogs (PBAs) are notable for their open framework, structural robustness, and adaptability to various ions. Despite their advantages, challenges such as the irreversible phase transitions upon cycling, low electrical conductivity, and abundant defects and crystal water impede the broader application of PBAs in ZHIBs. This review discusses the advantages of PBA cathodes, comprehensively summarizing the challenges encountered and proposing corresponding strategies aimed to these challenges. Recent applications of PBAs in ZHIBs are summarized, highlighting their potential and limitations. Finally, the review outlines the opportunities and challenges facing the field, proposing potential research pathways to further develop PBA cathodes for ZHIBs.

The design of green and low-cost Z-scheme heterojunctions with the interfacial electric field (IEF) is of prime importance to their photocatalytic hydrogenation performance and practical application. In this work, we construct a novel Z-scheme heterojunction photocatalyst comprised of Zn-Ni₂P/g-C₃N₄ nanosheets for hydrogen evolution reaction (HER). Experimental results and density functional theory calculations demonstrate that the construction of Z-scheme Zn-Ni₂P/g-C₃N₄ heterostructure not only promotes the generation of IEF directing from Zn-Ni₂P to g-C₃N₄, along with work function, accelerating the photogenerated charge separation in Zn-Ni₂P/g-C₃N₄, but also leads to the upshift of the p-band state density in Zn-Ni₂P/g-C₃N₄, favorable for the H* adsorption toward HER. The Zn-Ni₂P/g-C₃N₄ photocatalyst demonstrated excellent photocatalytic HER activity, with a hydrogen production rate of up to 1077 µmol g⁻¹ h⁻¹ and a stability of 49 h. Our findings provide a new method to enhance the separation of photogenerated charges. This improvement boosts the photocatalytic properties of solar-driven materials and devices.

Glucose metabolism reprogramming has emerged as a hallmark of cancer. We have reported that high temperature food or drink (>65°C) is the key etiological factors contributing to esophageal squamous cell carcinoma (ESCC) progression. Intriguingly, we observed that heat stimulation (42°C) alters glycolytic pathways in esophagus cells, but the underlying mechanisms remain poorly understood. Our findings revealed that stress-induced phosphoprotein 1 (STIP1) exhibits elevated expression in esophageal tissues exposed to heat stimulation (>65°C) compared to unexposed tissues, and its overexpression correlated with clinical grade and predict poor prognosis in ESCC patients. Mechanistically, STIP1 interacts with and activates adenosylhomocysteinase (AHCY; also termed SAHH) and change the conformation of AHCY. STIP1 also facilitates AHCY binding to lactate dehydrogenase A (LDHA), stimulating glycolysis. Notably, AHCY recruits protein arginine methyltransferase 3 (PRMT3) to methylate LDHA at R106, inhibiting ubiquitination-mediated AHCY degradation. In vivo, STIP1 knockout in mice dramatically inhibits 4-nitrochinoline-oxide (4NQO) induced esophageal tumorigenesis. Through virtual screening and functional validation, we identified licochalcone A (LCA) as a potent inhibitor of STIP1-driven ESCC proliferation in vitro and in vivo. In summary, these findings delineate a pro-tumorigenic signaling pathway whereby heat-induced STIP1 upregulation promotes ESCC glycolysis and growth via moonlighting functions that coordinate AHCY activity and LDHA methylation.

Flexible ionic conductive electrodes, as a fundamental component for electrical signal transmission, play a crucial role in skin-surface electronic devices. Developing a skin-seamlessly electrode that can effectively capture long-term, artifact-free, and high-quality electrophysiological signals remains a challenge. Herein, we report an ultra-thin and dry electrode consisting of deep eutectic solvent (DES) and zwitterions (CEAB), which exhibit significantly lower reactance and noise in both static and dynamic monitoring compared to standard Ag/AgCl gel electrodes. Our electrodes have skin-like mechanical properties (strain-rigidity relationship and flexibility), outstanding adhesion, and high electrical conductivity. Consequently, they excel in consistently capturing high-quality epidermal biopotential signals, such as the electrocardiogram (ECG), electromyogram (EMG), and electroencephalogram (EEG) signals. Furthermore, we demonstrate the promising potential of the electrodes in clinical applications by effectively distinguishing aberrant EEG signals associated with depressive patients. Meanwhile, through the integration of CEAB electrodes with digital processing and advanced algorithms, valid gesture control of artificial limbs based on EMG signals is achieved, highlighting its capacity to significantly enhance human-machine interaction.

Asymmetrical pleated textile with unidirectional water transport plays a vital role in maintaining personal moisture and thermal comfort. Inspired by the cactus branch, in this work, an asymmetrical pleated structure textile embedded with a unidirectional water transport channel was proposed by seamless weft knitting technology. This innovative textile with differential capillary effect can swiftly transport water within 1 s, with an accumulative one-way transport index (AOTI) of 499.57%. This textile also exhibits excellent external water repellency with a stable contact angle exceeding 120°. Most importantly, water repellency, water collection, and directional water transport ability are integrated into one unified system by means of the asymmetrical pleated structure, thereby ensuring both safety and comfort for the wearer. The advanced fabrics meet high transmission indexes and fast transport rates, which are expected to provide a fresh avenue for the development and creation of more efficient and adaptive personal moisture and thermal management fabrics.

Protecting neuronal mitochondria by eliminating the mitochondrial ROS (mtROS) storm is crucial to abrogate the neuronal damage cascade of ischemic stroke ischemia reperfusion (ISIR), which is a long-standing challenge in the field of ischemic stroke (IS). Existing blood-brain barrier (BBB) penetration methods are usually unable to distinguish between healthy brain tissue and cerebral infarction tissue, and BBB targeting is not compatible with mitochondrial targeting, resulting in a huge barrier to the specific elimination of mtROS in neuronal mitochondria in ISIR. This study introduces an elegantly designed tannic acid, polydopamine, and Mo-based heteropolyacid ternary composite nanomedicine (TPM), which not only has a superb ability to eliminate multiple ROS thanks to the introduction of polydopamine, but also can actively recognize the injured BBB site, specifically enter the neurons in the cerebral infarction area, and then highly specifically target the mitochondria of neurons to efficiently eliminate mtROS. TPM could significantly inhibit neuronal apoptosis by protecting mitochondria and eliminate inflammation by inhibiting activation of the STING pathway, thereby significantly reducing the size of cerebral infarction. This sequential targeting of TPM from the injured BBB to neuronal mitochondria provides a promising strategy to treat ISIR in the clinical setting.

Reactive oxygen species (ROS) have gained increasing attention in electrochemiluminescence (ECL) as endogenous co-reactants, yet their application in the most widely used tris(bipyridine)-ruthenium(II) system remains limited due to the scarcity of suitable co-reactant accelerators (CRAs) with selective oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalytic activity. Here, this work reports a series of facet-tunable homogeneous NiNPs catalysts, which can stimulate ECL at distinguishable cathodic/anodic potentials in tris(bipyridine)-ruthenium(II) system. Experimental studies and theoretical calculation results reveal that the Ni(1 1 0) surface, with its lower charge density, impedes the fourth step of 4e⁻ ORR, thus favoring 2e⁻ pathway and consequently promoting substantial ROS generation and ECL at the cathode. Conversely, the Ni(1 1 1) and (2 0 0) surface prompt robust and stable anodic ECL via hydroxyl radical by controlling the OER. These excellent CRAs link cathodic/anodic ECL with ORR/OER, offering a novel strategy for precisely designing predictable non-precious metal CRAs. Furthermore, sensitive immunosensors were developed using these CRAs, demonstrating successful application in potential-resolved ECL analysis for practical purposes.

Sepsis and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Immunoparalysis plays a vital role in the pathophysiological progression of sepsis, leading to intracellular persistent infections and high mortality of septic patients. Eradicating intracellular infections and rescuing immunoparalysis are critical for sepsis management, yet effective tactics remain elusive. Here, we report immunomodulatory nanozymes (named PdIr@OMVs) that enable intracellular bacteria elimination and reinvigorate systemic innate-adaptive immune response during immunoparalysis to tackle multidrug-resistant (MDR) bacterial sepsis. The PdIr@OMVs are designed by encapsulating plasmonic PdIr nanocatalysts with immunostimulants of biocompatible bacterial outer membrane vesicles (OMVs). PdIr@OMVs exhibit unique localized surface plasmon response-enhanced peroxidase-like catalytic activity, and inherit the remarkable immunocyte-targeting capability and adjuvanticity of OMVs. We demonstrate that PdIr@OMVs not only potentiate the phagolysosomal killing effect of impaired macrophages via in situ catalysis to eradicate intracellular MDR bacteria and burst antigen release, but also allow rapid activation/maturation of dendritic cells to boost the presentation of bacterial antigen and orchestrate innate-adaptive immunity for rescuing immunoparalysis. In two immunocompromised mouse models of MDR bacterial sepsis, PdIr@OMVs collaboratively reduce bacterial burden and restore immune homeostasis, thereby circumventing organ damage and enabling the recovery of septic mice. Our work offers a promising therapeutic modality for sepsis and septic shock.