Single-cell mass spectrometry enables label-free and high-throughput molecular analysis of individual cells. However, conventional vacuum-based secondary ion mass spectrometry (SIMS) faces challenges in probing metabolism of single living cells under native physiological conditions. Here, we introduce a liquid SIMS platform coupled with a vacuum-compatible cell-culture device, which allows in-situ metabolomic profiling of single living cells in their native culture environment without any pretreatment. This platform uniquely enables direct nanoscale interfacial characterization, and we report for the first time the determination, via MS depth profiling, of a lipid bilayer with a SiN-equivalent thickness of ∼8.6 nm in a single living human nonsmall cell lung cancer (A549) cell. As a proof of concept, we applied this method to investigate metabolomic changes linked to cisplatin resistance in A549 cells. Our findings indicate upregulation of cholesterol, phosphatidylcholine, and low-unsaturation fatty acids in resistant cells, and we demonstrate that inhibiting cholesterol synthesis effectively reduces drug resistance. This work underscores the potential of liquid SIMS for in-situ metabolic profiling during complex biological processes.

The spatial heterogeneity of pathological factors in diabetic chronic wounds (DCWs) limits the development of effective treatment strategies. Here, a hydrogel-based wound dressing integrated with a dissolving microneedle array (H@MN) that orchestrates a novel spatiotemporal cascade reaction strategy is presented. Compared to the classical temporal cascade reaction, the spatiotemporal cascade reaction is characterized by spatially compartmentalized catalysts, which rely on the cross-regional diffusion of initial reaction products to the subsequent catalyst site to drive the sequential catalytic processes. Targeting the pathological features of DCWs, the glucose oxidase (GOX)-, superoxide dismutase (SOD)-, and catalase (CAT)-catalytic reactions are selected, which are catalyzed by natural enzymes or nanozymes. By integrating these catalysts into a spatiotemporal cascade reaction within the H@MN, it can intervene in and dynamically modulate the pathological factors in different spatial domains of DCWs at various temporal stages. Both in vitro and in vivo experiments confirm that the H@MN-enabled spatiotemporal cascade reaction, when combined with photothermal therapy, achieves superior healing efficacy in DCWs. The H@MN-enabled spatiotemporal cascade reaction is believed to inspire a generalizable strategy for treating diverse diseases characterized by spatially varied pathological microenvironments, offering a promising paradigm for advanced therapeutics.

Drug-resistant bacterial infections in wounds represent a major clinical challenge associated with bacterial persistence, oxidative stress, and immune dysregulation. To effectively manage these issues, we developed a multifunctional composite hydrogel (Pae-BP@Gel) by incorporating paeonol-loaded black phosphorus nanosheets (BP) into a glycidyl methacrylate-modified gelatin matrix for the treatment of infected wounds. Upon near-infrared region (NIR) irradiation, Pae-BP@Gel produces photothermal heat that disrupts bacteria, while paeonol and BP further contribute to bacterial membrane damage and antibacterial activity. Notably, Pae-BP@Gel demonstrates antioxidant activity through paeonol and BP, which cooperatively scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS). This restoration of redox homeostasis, combined with efficient drug-resistant bacterial clearance, improves the wound microenvironment and promotes macrophage polarization toward the prohealing M2 phenotype, facilitating inflammation resolution and angiogenesis. In vivo studies in methicillin-resistant Staphylococcus aureus-infected wound models demonstrate that Pae-BP@Gel significantly accelerates re-epithelialization, enhances collagen deposition, and promotes comprehensive tissue repair. This composite hydrogel thus provides a safe, multifunctional, and efficient strategy for clinical applications in drug-resistant bacterial-infected wound repair.

TROP2 has emerged as a significant biomarker and therapeutic target in various epithelial cancers, owing to its tissue-specific expression and its association with tumor proliferation, invasion, and metastasis. Tumor cell migration is a critical determinant of tumor invasiveness and malignancy, serving as a pivotal factor in prognosis assessment and therapeutic response evaluation. Despite these insights, the molecular mechanisms underpinning TROP2's role in tumor progression─particularly in mediating tumor cell migration─remain incompletely understood. Desmosomes, as essential cell-cell adhesion structures, are integral to maintaining tissue architecture; however, how subtle alterations in their expression and structural organization influence tumor cell adhesion warrants further investigation. In this study, we employed direct stochastic optical reconstruction microscopy (dSTORM) coupled with biochemical approaches to elucidate the mechanism by which TROP2 regulates tumor cell migration via desmosomal cadherin DSG2. Co-localization imaging and coimmunoprecipitation assays confirmed an interaction between TROP2 and DSG2. By establishing TROP2 overexpression and knockdown cell lines, we observed that high TROP2 expression not only downregulated DSG2 levels but also impaired desmosome assembly. These findings were further confirmed at the tissue level. Moreover, we found that TROP2 facilitated tumor cell proliferation and migration by suppressing DSG2 expression and activating EGFR/AKT and FAK downstream signaling pathways. Our findings reveal the molecular mechanism by which TROP2 promotes migration, highlighting the critical role of intercellular junction integrity in cancer progression. These insights provide a foundation for developing targeted therapies against TROP2 and its associated signaling mechanisms in epithelial malignancies.

Nonadiabatic effects profoundly influence lattice dynamics, resulting in phonon renormalizations not only at the center of Brillouin zone (BZ), but also across the entire dispersion at finite momenta. These nonadiabatic phenomena exhibit clear dimensional dependencies and remain largely unexplored experto investigate nonadiabatic phonon dispersion renormalization in monolayer graphene (MLG) and Bernal bilayer graphene (BLG). We present comprehensive phonon spectra measurements for both MLG and BLG across the full BZ. The high-resolution data reveal an intriguing "W" -shaped dispersion for the longitudinal optical phonon in MLG and a "V" -shaped dispersion in BLG near the BZ center, in contrast to the conventional "U" -shaped parabolic dispersions. Combining theoretical analysis, these anomalous phonon renormalizations are demonstrated to originate from nonadiabatic electron-phonon couplings. The comparative study of MLG and BLG gives a generic understanding of the impact of nonadiabatic effects on phonon dispersions in doped two-dimensional systems.

Infected wound healing is a multifaceted biological process, particularly in the context of the emergence of antibiotic-resistant bacteria that compromise the efficacy of conventional treatments, thereby rendering the management of infected wounds exceedingly challenging. Developing highly effective antibacterial materials to fight resistant bacteria and promote wound healing remains a major challenge. In this study, a graphene oxide (GO)-based synergistic multifunctional nanomaterial, GO-Ag-l-Arg, is developed to promote wound healing by effectively combating antibiotic-resistant bacterial infections and promoting angiogenesis. The excellent antibacterial activity of GO-Ag-l-Arg is attributed to the synergistic effect of highly dispersed silver nanoparticles (Ag NPs) and l-Arginine (l-Arg). GO-Ag-l-Arg can effectively avoid the aggregation of Ag NPs and fully exert the antibacterial ability of Ag NPs in GO-Ag-l-Arg. By precisely regulating the pH, l-Arg is further loaded onto the GO-Ag nanosheets through an esterification reaction between the hydroxyl on the surface of GO and l-Arg. The highly positively charged guanidyl in l-Arg can interact with negatively charged bacteria, improving the targeting ability between the nanocomposite and bacteria and further enhancing the antibacterial effect of GO-Ag-l-Arg. At the same time, GO-Ag-l-Arg can produce nitric oxide (NO) under the action of cells, thus effectively promoting angiogenesis. The in vivo experiments show GO-Ag-l-Arg exhibits an outstanding ability to accelerate the healing of bacterial-infected wounds by inhibiting bacterial growth and stimulating angiogenesis at the wound site, offering a promising strategy for the treatment of wounds infected by drug-resistant bacteria.

Tumor immunotherapy has shown considerable therapeutic potential, especially when combined with chemotherapy. In this study, we developed a multifunctional nanoplatform GNPs-DOX/R848 that combined immunotherapy and chemotherapy for the treatment of melanoma, in which gelatin nanoparticles (GNPs) were loaded with the immunomodulatory agent resiquimod (R848) and the chemotherapy drug doxorubicin (DOX). GNPs possessed inherent immunomodulatory properties; when combined with R848, they induced a more pronounced polarization of M1-like macrophages by activating the NF-κB signaling pathway, thereby reversing the immunosuppressive tumor microenvironment. Meanwhile, GNPs effectively delivered R848 and DOX to tumor cells, promoting stronger therapeutic effects of the drugs, which strongly induced the immunogenic cell death triggered by DOX, leading to the infiltration of T cells into the tumor tissue. The treatment of melanoma demonstrated that GNPs-DOX/R848 significantly reduced tumor volume, enhanced the therapeutic effects of chemotherapy, providing a new approach for the combined treatment of cancer with immunotherapy and chemotherapy.

Angiogenesis is an important physiological process in the human body. When ischemic diseases occur, the ischemic and hypoxic environment induces excessive production of reactive oxygen species (ROS) within cells, which inhibits angiogenesis and leads to poor prognosis. Therefore, finding antioxidants that can eliminate excessive ROS to promote angiogenesis is crucial for the treatment of ischemic diseases. In this work, we investigate the antioxidant effects of dimethyl itaconate (DMI) by using an oxidative stress model in human umbilical vein endothelial cells (HUVECs). Our results demonstrate that DMI significantly reduces excessive ROS in cells under oxidative stress. DMI could protect mechanical properties of HUVECs from oxidative stress. The Young's modulus of HUVECs was 10.0 ± 1.4 kPa after treatment with H2O2. However, the Young's modulus increased to 24.42 ± 1.4 kPa when HUVECs were co-incubated with H2O2 and DMI (40 μg mL-1). DMI also maintained cell morphology and cytoskeletal integrity. Meanwhile, DMI alleviates mitochondrial dysfunction by enhancing mitochondrial membrane potential (MMP) and increasing adenosine triphosphate (ATP) levels. The excellent antioxidant effects of DMI result from upregulating the expression levels of superoxide dismutase 2 and catalase, significantly leading to the removal of intracellular excessive ROS. With protecting HUVECs from oxidative stress damage, DMI promotes cell migration and angiogenesis. Consequently, this work not only elaborates on the mechanism by which DMI promotes angiogenesis by anti-oxidative stress, but also provides a new therapeutic option for the treatment of ischemic diseases.

The treatment of persistent drug-resistant bacterial infections in wounds poses a significant global medical challenge. Developing innovative antimicrobial strategies capable of simultaneously achieving bacterial eradication, inflammation resolution, and tissue regeneration has become imperative. Herein, a nanocomposite featuring plasma-enhanced enzymatic activity and immunoregulatory properties is engineered, designed to reprogram the wound microenvironment and expedite healing in drug-resistant bacterial infections. Capitalizing on the localized surface plasmon resonance effect of Au@Ag nanoparticles coupled with the pH-dependent peroxidase-like (POD-like) activity of cerium dioxide (CeO2), the BSA-(Au@Ag/CeO2) nanocomposites orchestrate dual-modality photothermal-chemodynamic therapy for enhanced bactericidal efficacy and biofilm disruption. Upon near-infrared laser irradiation, plasmon-generated hot electrons are transferred to CeO2, triggering massive reactive oxygen species production via enhanced POD-like catalysis. This synergistic dual-action mechanism eradicates methicillin-resistant Staphylococcus aureus (MRSA) through membrane disruption and reactive oxygen species (ROS)-induced oxidative stress. Remarkably, the nanosystem not only suppresses proinflammatory cytokine storms but also steers macrophage polarization toward tissue reparative M2 phenotypes at infection sites, thereby alleviating pathological inflammation and fostering regenerative microenvironments. Biosafety assessments confirm the absence of discernible toxicity in vital organs. This multifunctional platform represents a paradigm-shifting strategy for managing antibiotic-resistant wound infections, providing a clinically translatable solution to combat antimicrobial resistance.

Tooth whitening has attracted considerable attention as it can enhance appearance and improve oral health. Nanocatalysts with peroxidase-like activity can catalyze H2O2 to generate reactive oxygen species (ROS), a process known as chemodynamic therapy (CDT). The ROS generation can achieve effective tooth whitening and caries prevention. Nonetheless, traditional CDT methods often struggle with controlling the reaction process by adjusting the concentrations of H2O2 or nanocatalysts. An excessive ROS can harm oral tissues, whereas insufficient ROS may compromise therapeutic efficacy. To address this issue, this study designed a hydrogel bilayer that separately encapsulates H2O2 and iron-based metal-organic frameworks (Fe-MOFs) nanoparticles (NPs) with peroxidase-like activity. The ROS generation was regulated by leveraging the concentration-gradient diffusion of H2O2. Through Monte Carlo simulations and machine learning algorithms, mathematical formulas were derived to elucidate how to harness concentration-gradient diffusion for near-independent modulation of the reaction half-life and rate. The experimental results demonstrated that being guided by the formulas could effectively avoid the initial burst of ROS and manipulate the ROS generation duration, thereby achieving safe and effective tooth whitening and caries prevention. We anticipate that this bilayer design strategy can be extended to other CDT systems, enabling precise control over therapeutic outcomes.

Chronic wounds infected with drug-resistant bacteria present a formidable clinical challenge, exacerbated by antibiotic overuse that severely compromises healing. Herein, a multifunctional therapeutic hydrogel wound dressing is developed to address these challenges. This advanced nanocomposite hydrogel incorporates cerium dioxide-doped MXene nanosheets (MXene@CeO2) within a glycidyl methacrylate-modified gelatin (GMA-Gelatin) matrix and crosslinked into a hydrogel under UV irradiation (GMAG-GEL), forming a near-infrared (NIR)-responsive material (MXene@CeO2/GMAG-GEL). This incorporation enhances the mechanical strength of the hydrogel and creates a protective microenvironment for wound repair. In the acidic environment of bacterial infections, MXene@CeO2/GMAG-GEL facilitates the electrostatic capture of bacteria. Synergizing with its photothermal capability, it exhibits exceptional antibacterial activity, effectively killing drug-resistant bacteria and disrupting bacterial biofilms. After eradicating the infection, MXene@CeO2/GMAG-GEL further alleviates oxidative stress, promotes cell migration and angiogenesis, and induces macrophage polarization toward an anti-inflammatory phenotype. In vivo studies confirmed MXene@CeO2/GMAG-GEL significantly accelerates wound closure and tissue regeneration. This work overcomes the key challenges of antibiotic resistance, persistent inflammation, and impaired tissue regeneration, presents a comprehensive therapeutic strategy for drug-resistant bacterial wound infections through a single multifunctional platform.

The mechanical properties of nanocarriers and the ability of tumor cells to sense mechanical cues are critical factors in regulating cellular internalization. During epithelial-mesenchymal transition (EMT), tumor cells undergo changes that enhance their invasiveness, but how these changes affect their ability to sense mechanical cues, thereby impacting drug delivery efficiency and treatment effects, is still unknown. Here, we synthesized chitosan nanoparticles (CSNPs) with different Young's moduli ranging from 0.325 to 18.25 MPa. Our findings revealed that as EMT progresses, tumor cells exhibited enhanced internalization capacity, attributing to the elevated integrin expression by EMT. During the cellular internalization of CSNPs with different Young's moduli, the stiffer CSNPs displayed more internalization in tumor cells. It was due to the upregulation of p-FAK expression after the integrin of cells sensed stronger mechanical cues generated by stiffer CSNPs, resulting in promoted F-actin polymerization, ultimately achieving more cellular internalization. After loading doxorubicin (DOX) into CSNPs (DOX-CSNPs), the stiffer DOX-CSNPs exhibited higher inhibitory ability, with mesenchymal phenotype tumor cells displaying the highest treatment effect. Taken together, our work demonstrated how the mechanical properties of nanocarriers affect cellular internalization across different EMT stages and provided a mechanical-based nanocarrier engineering strategy for cells undergoing EMT.

The emergence of drug-resistant bacteria has rendered traditional antibiotics ineffective, posing a serious threat to human health. There is an urgent need to find alternative antimicrobial agents. Inspired by enzyme immobilization and multi-enzyme biocatalysis, we have designed a tri-metal layered double hydroxide (LDHs)-based cascade catalytic system (CoCuFe-LDH@Gox nanosheets) for treating drug-resistant bacterial infections and promoting wound healing. The synergistic effects of the Co, Cu, and Fe in the tri-metal LDHs structure endow CoCuFe-LDH nanosheets with excellent peroxidase (POD)-like activity. The large specific surface area of CoCuFe-LDH nanosheets render them ideal carriers for glucose oxidase (Gox). CoCuFe-LDH@Gox nanosheets can catalyze glucose to produce gluconic acid and H2O2. The generated gluconic acid decreases the local pH, further enhancing the POD-like activity of CoCuFe-LDH@Gox nanosheets at wound site. CoCuFe-LDH@Gox nanosheets can then catalyze H2O2 generating hydroxyl radicals (•OH) to effectively kill drug-resistant bacteria. This synergistic integration of the catalytic LDHs and the Gox components enables the cascade catalytic system to be highly effective against drug-resistant bacteria. In addition to its remarkable antibacterial properties, this LDHs-based system also exhibits excellent biocompatibility and considerable immunomodulatory capabilities. It can accelerate the healing of drug-resistant bacteria-infected wounds by inhibiting the inflammatory response and regulating macrophage polarization. These multifunctional attributes make the CoCuFe-LDH@Gox nanosheets a highly promising candidate for the treatment of drug-resistant bacterial infections in future clinical applications.

Topological phonons associated with nontrivial edge states open a new avenue to explore interesting quasi-particles excitations and manipulate phonon transportations. Although kinds of topological phonons associated with their promising device applications have been theoretically predicted, experimentally observing nontrivial edge states is still absent owing mainly to the challenges in simultaneously achieving sufficient sensitivity and space, momentum, and energy resolutions for detecting the highly localized edge phonon mode. Here, with delicately balanced space and momentum resolutions of electron energy loss spectroscopy in a scanning transmission electron microscope, we realize the direct observation of topologically nontrivial phononic edge states of graphene in momentum and real space. Two types of two-fold degenerate edge states, induced respectively by Dirac point and nodal ring, are explicitly observed at the Brillouin zone boundary M point, and highly localized at the edge in real space, which are in excellent agreement with the theoretical predictions. The verification of topological phononic edge states and the demonstrated detection method are crucial to the field of topological phonons, promoting quasiparticles-phonon coupling explorations, thermal transportation studies, and novel phonon device developments.

Tumor-associated epithelial-mesenchymal transition (EMT) contains a set of transitional cellular states usually judged by the EMT marker expression. E-cadherin is a down-regulated EMT epithelial marker, and the detection of E-cadherin is challenging on cancer cell surfaces in the middle and late stages of EMT. Here, the trace E-cadherins on the living bladder cancer T24 cell surface during EMT were investigated with force-distance curve-based atomic force microscopy. The results confirmed that T24 cells are still in an intermediate state and can be transferred into the mesenchymal phenotype by long-term TGF-β1 induction. During EMT, E-cadherins on the T24 cell surface gradually decreased and rarely clustered. E-cadherin is not completely missing, even at the end of EMT, but is too sparse to cluster. This work provides us with a visual understanding of the expression and distribution of trace markers during EMT and a deep comprehension of the indispensable significance of E-cadherin in cancer cells.

AbstractMicron-sized Si anode promises a much higher theoretical capacity than the traditional graphite anode and more attractive application prospect compared to its nanoscale counterpart. However, its severe volume expansion during lithiation requires solid electrolyte interphase (SEI) with reinforced mechanical stability. Here, we propose a solvent-induced selective dissolution strategy to in situ regulate the mechanical properties of SEI. By introducing a high-donor-number solvent, gamma-butyrolactone, into conventional electrolytes, low-modulus components of the SEI, such as Li alkyl carbonates, can be selectively dissolved upon cycling, leaving a robust SEI mainly consisting of lithium fluoride and polycarbonates. With this strategy, raw micron-sized Si anode retains 87.5% capacity after 100 cycles at 0.5 C (1500 mA g−1, 25°C), which can be improved to >300 cycles with carbon-coated micron-sized Si anode. Furthermore, the Si||LiNi0.8Co0.1Mn0.1O2 battery using the raw micron-sized Si anode with the selectively dissolved SEI retains 83.7% capacity after 150 cycles at 0.5 C (90 mA g−1). The selective dissolution effect for tailoring the SEI, as well as the corresponding cycling life of the Si anodes, is positively related to the donor number of the solvents, which highlights designing high-donor-number electrolytes as a guideline to tailor the SEI for stabilizing volume-changing alloying-type anodes in high-energy rechargeable batteries.

Transferred graphene provides a promising III-nitride semiconductor epitaxial platform for fabricating multifunctional devices beyond the limitation of conventional substrates. Despite its tremendous fundamental and technological importance, it remains an open question on which kind of epitaxy is preferred for single-crystal III-nitrides. Popular answers to this include the remote epitaxy where the III-nitride/graphene interface is coupled by nonchemical bonds, and the quasi-van der Waals epitaxy (quasi-vdWe) where the interface is mainly coupled by covalent bonds. Here, we show the preferred one on wet-transferred graphene is quasi-vdWe. Using aluminum nitride (AlN), a strong polar III-nitride, as an example, we demonstrate that the remote interaction from the graphene/AlN template can inhibit out-of-plane lattice inversion other than in-plane lattice twist of the nuclei, resulting in a polycrystalline AlN film. In contrast, quasi-vdWe always leads to single-crystal film. By answering this long-standing controversy, this work could facilitate the development of III-nitride semiconductor devices on two-dimensional materials such as graphene.

Machine learning (ML) coupled with quantum chemistry calculations predicts catalyst properties with high accuracy; however, ML approaches in the design of multicomponent catalysts primarily rely on simulation data because obtaining sufficient experimental data in a short time is difficult. Herein, we developed a rapid screening strategy involving nanodroplet-mediated electrodeposition using a carbon nanocorn electrode as the support substrate that enables complete data collection for training artificial intelligence networks in one week. The inert support substrate ensures intrinsic activity measurement and operando characterization of the irreversible reconstruction of multinary alloy particles during the oxygen evolution reaction. Our approach works as a closed loop: catalyst synthesis-in situ measurement and characterization-database construction-ML analysis-catalyst design. Using artificial neural networks, the ML analysis revealed that the entropy values of multicomponent catalysts are proportional to their catalytic activity. The catalytic activities of high-entropy systems with different components varied little, and the overall catalytic activity was greater than that of the medium-low-entropy system. These findings will serve as a guideline for the design of catalysts.

Bubble-free bilayer graphene has been fabricated by directly dry-laminating the clean backsides of two single graphene layers with designed asymmetric transfer media.

With excellent electrochemical activity, low con-sumption, and easy synthesis, Co-based layered double hydroxides (LDHs) have been applied to electrochemical energy conversion and storage devices. Understanding the mechanisms of morpho-logical evolution and capacity changes under potential cycles is critical for the design of high-performance materials of Co-based LDHs. Here, we monitored the morphological evolution of two kinds of CoFe-LDH nanosheets and four kinds of CoAl-LDH nanosheets using in situ electrochemical-atomic force microscopy. The CoFe-LDH nanosheets present the growth of granular particles and the deterioration of capacity performances, which might be due to the irreversible conversion of hydroxide into oxyhydroxide under potential cycles. The CoAl-LDH nanosheets maintain more capacity and do not form granular particles under potential cycles, resulting from the electrochemical reaction reversibility of Co2+ and the stability of the host hydroxide layer enhanced by Al3+. The introduction of Al3+ into the Co-based LDH structure is conducive to cyclic stability of capacity compared to that of Fe3+. Additionally, the CoAl-LDH nanosheets with different Co/Al molar ratios present varying degrees of dissolution and variations of capacity under potential cycles. A moderate Co/Al molar ratio of CoAl-LDH nanosheets is beneficial to cyclic stability. These findings would provide a deep insight into the mechanisms of capacity changes based on in situ morphological evolution and support for the optimization of such material performance.