Glypican-3 (GPC3) is a heparan sulfate proteoglycan that is highly expressed in hepatocellular carcinoma and promotes tumor progression through Wnt3a/β-catenin signaling. However, how the nanoscale organization of GPC3 at the cell surface controls signaling remains unclear. Here, we combined nano-resolution MINFLUX imaging, single-molecule tracking, and functional assays to define the spatial architecture and dynamics of GPC3 on hepatoma cells. We found that GPC3 exists as both single molecules and nanoscale clusters and switches between confined and free diffusions on the plasma membrane. Heparan sulfate (HS) chains create nanoscale corrals that limit GPC3 movement, whereas removal of HS increases diffusive heterogeneity and disrupts confinement. Wnt3a stimulation induces the formation of higher-order GPC3 assemblies and enhances β-catenin signaling, while loss of HS markedly reduces this response. MINFLUX DNA-PAINT further revealed that HS chains orchestrate the spatial distribution of Wnt3a and promote its association with the Wnt receptor, Frizzled-1, an essential step for pathway activation. Collectively, these findings reveal that HS controls the nanoscale organization and dynamics of GPC3 to promote Wnt receptor assembly and efficient β-catenin signaling in hepatoma cells.
Mixed-cation lead mixed-halide perovskites are promising materials for applications in photovoltaics; however, it has been suggested that they exhibit instabilities linked to nanoscale heterogeneity. Directly probing the origins of this heterogeneity requires characterization with nanoscale spatial resolution, making transmission electron microscopy (TEM) an essential tool. However, characterizing these materials is challenging due to their extreme sensitivity to electron irradiation. Here, we develop a low-dose, concurrent methodology using four-dimensional scanning transmission electron microscopy (4D-STEM) and energy-dispersive x-ray spectroscopy (EDX) in order to map both the chemical and structural architecture of a (FA0.83Cs0.17)Pb(I0.8Br0.2)3 perovskite film without inducing damage. Our correlative analysis reveals a complex mosaic of coexisting crystal structures in this state-of-the-art LHP film. We establish a direct link between local chemical composition and crystal structure, showing that the formation of undesirable, photovoltaically inactive hexagonal polytypes is predominantly driven by local deficiencies in the stabilizing cesium cation. These findings provide crucial insight into one of the fundamental origins of structural instabilities in mixed composition perovskite thin-films, suggesting that achieving long-term device performance requires the development of fabrication routes that ensure compositional homogeneity at the nanoscale.
Nanoscale collagen remodeling is a critical physical signature of tumor development and metastasis. Recently, we have shown that vibrational sum-frequency generation (VSFG) microscopy can detect tumor tissues prepared from Optimal Cutting Temperature (OCT) samples, where this unique sensitivity to nanostructure comes from mode-specific coherent interference. Yet, most clinical tissues are processed as formalin-fixed, paraffin-embedded (FFPE) blocks, which remains unknown whether these harsh fixations and embedding processes destroy the subtle structural cues that VSFG detects. Thus, it could present a large barrier for further application of VSFG broadly into biophysics and biomedical research of tumors. Here, we demonstrate that VSFG remains fully effective in deparaffinized FFPE tissues. Crucially, following deparaffinization, key diagnostic metrics were statistically indistinguishable from OCT cryosection controls. These metrics included VSFG spectra, chemical images, and the collagen ratio I NHs /I CH2 ,Ss . Complementary atomic force microscopy (AFM) nanomechanics corroborated this finding. These findings open the path of using VSFG imaging for standard clinical workflows and the vast global archives of FFPE tissues for retrospective prognostic studies and label-free diagnostics.
Pancreatic cancer remains one of the most aggressive malignancies with limited therapeutic options and poor prognosis. Erlotinib (OSI-774), a small-molecule tyrosine kinase inhibitor (TKI), is clinically used in combination with gemcitabine, yet its efficacy is limited by modest improvements in overall survival (OS) and significant side effects. The aggregation of erlotinib in aqueous solutions further restricts its bioavailability. This study investigates the potential of Congo red (CR), a supramolecular carrier, to enhance the therapeutic impact of erlotinib against pancreatic cancer cells. Biophysical analyses using UV-visible spectroscopy (UV-Vis) and dynamic light scattering (DLS) confirmed the formation of stable CR-erlotinib co-aggregates with optimal molar ratio of 5:1. The effects of erlotinib alone and in combination with CR (CR:OSI-774) were evaluated on two pancreatic cancer cell lines (PANC-1 and BxPC-3). CR:OSI-774 complexes demonstrated significantly lower IC50 and IC90 values compared to erlotinib monotherapy, indicating enhanced anti-proliferative effects. While erlotinib induced apoptosis, CR:OSI-774 primarily triggered necrotic cell death. Importantly, both compounds significantly inhibited cancer cell migration and invasion, with CR:OSI-774 showing superior inhibition of invasive capacity. CR alone did not negatively affect cell viability or apoptosis/necrosis rates. Nanomechanical measurements using atomic force microscopy revealed an increase in cellular stiffness after treatment, particularly in cells exposed to the CR-erlotinib complex, suggesting changes in cytoskeletal organization associated with reduced motility. Furthermore, quantitative protein analysis using the Jess capillary electrophoresis system revealed a decrease in AKT phosphorylation without significant changes in total AKT levels, indicating effective modulation of EGFR signaling via supramolecular aggregation. These findings suggest that supramolecular aggregation with CR represents a promising strategy to enhance erlotinib efficacy in pancreatic cancer therapy while potentially reducing systemic toxicity. The approach opens new avenues for personalized medicine and targeted anti-cancer therapy.
Our Emerging Investigator Series features exceptional work by early-career nanoscience and nanotechnology researchers. Read Jake McClements's Emerging Investigator Series article 'Unlocking interstitial fluid for acute coronary syndrome diagnosis: ultrasensitive troponin I detection using imprinted polymer nanoparticles' (https://doi.org/10.1039/D5NH00441A) and read more about him in the interview below.
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With the rapid growth in energy demand, designing a novel hybrid battery system has become increasingly important. It is critical to reveal the coupling mechanisms of intercalation-conversion hybrid cathodes and provide an in-depth understanding of structure-performance relationships for the electrochemical energy storage devices with high energy density. In this study, a hybrid cathode that combines intercalation-type LiNixCoyMn1-x-yO2 (NCM) with conversion-type oxygen (O2) is proposed. Using in situ electrochemical atomic force microscopy (EC-AFM), we elucidate that the overlithiation of the NCM cathode enhances electronic conductivity and exposes abundant active sites during discharge, thereby inducing the formation of Li2O2. Electrochemical tests demonstrate that the contributions of intercalation and conversion reactions to capacity are rate-dependent, with lower rates favoring the intercalation-dominated electrochemical process. Further scanning transmission electron microscopy characterization indicates that, during prolonged cycling, oxygen vacancies in the NCM intercalation-type cathode serve as preferential sites for the conversion-type Li-O2 intermediates, significantly enhancing the cycling stability of the battery. Ultimately, by optimizing the mass ratio between the intercalation and conversion cathodes, an enhanced cycle stability is achieved. This study offers valuable insights into modulating battery performance through multimechanism reactions in hybrid battery systems.
Thermoelectric materials have received much attention for their ability to directly convert heat into electricity for energy-conversion applications. This work presents a complete study of the effect of antimony (Sb) substitutional doping on the thermoelectric transport properties of a GeTe system based on the DFT-NEGF framework. In this study, we investigated three different doping concentrations by substituting Ge atoms with Sb atoms, namely, 1Sb-doped, 2Sb-doped, and 3Sb-doped GeTe systems. The incorporation of Sb atoms dramatically changes the local atomic structure and electronic environment of the GeTe monolayer, which leads to remarkable changes in charge distribution, electronic structure and thermoelectric transport behaviour. To evaluate the thermoelectric response, two-probe device models are constructed for pristine and doped GeTe monolayers, and transport parameters such as electrical conductance, Seebeck coefficient, thermal conductivity, and figure of merit (ZT) are calculated. The results show that Sb substitution enhances the thermoelectric performance of GeTe, with the 2Sb-doped configuration exhibiting the highest ZT value of about 7.2 at 700 K. These findings demonstrate that Sb substitutional doping is an effective approach for improving the thermoelectric efficiency of two-dimensional GeTe-based devices.
Strong electric fields at air-water interfaces are widely invoked to explain accelerated interfacial chemistry, yet direct, probe-free evidence under evaporation-free conditions has remained challenging. Here, we confine aqueous solutions and air within ∼50 nm-diameter multiwalled carbon nanotubes to stabilize nanoscale air-water interfaces for three-dimensional transmission electron microscopy. Reconstructed multiphase structures reveal ∼10 nm gas domains separated from the nanotube walls by ultrathin water films spanning molecular to nanometer thicknesses. Curvature analysis yields Laplace and disjoining pressure distributions indicating a repulsive pressure of ∼10 MPa that prevents film collapse. This repulsion is consistent with an interfacial electric field on the order of several volts per nanometer, primarily associated with oriented water dipoles and potentially enhanced by the electric double layer. Consistent with this inferred field strength, the reduction of chloroauric acid (HAuCl4) to gold nanoparticles occurs exclusively within ∼2 nm of the interface. These results provide evidence for intense, spatially confined electric fields at air-water interfaces through the combined observations of strong non-Derjaguin-Landau-Verwey-Overbeek repulsive pressures and localized interfacial Au reduction and establish their fundamental role in nanoscale interfacial chemistry across chemical, environmental, and energy-relevant systems.
A critical challenge in the bench-to-bedside translation of controlled drug release strategies is the sharp decline in reaction efficiency as biological complexity increases. A platform capable of maintaining bioorthogonal-like drug release─remaining minimally perturbed by physiological environments─would address an unmet clinical need. This is particularly relevant for radiotherapy-mediated drug release, where the oxidative activation of prodrugs is often compromised by the rapid quenching of reactive intermediates in vivo. Herein, we engineer a hafnium-based nanoscale metal-organic layer platform that leverages a unique "surface-confinement effect" to overcome this challenge. By covalently tethering prodrugs to the Hf-nMOLs surface, we constructed two-dimensional nanoreactors that spatially localize the activation process within an interface enriched with reactive species. This design effectively insulates the activation step from biological scavengers, ensuring efficient payload release efficiency across increasing biological complexity. When loaded with the topoisomerase I inhibitor Exatecan, the Hf-nMOLs system achieved an intratumoral drug-release G-value of 568 nM·Gy-1, resulting in potent radiosensitization and significant tumor-growth suppression under low-dose X-ray irradiation. This work presents a versatile strategy for robust radio-chemotherapeutic combinations, achieving the simultaneous release of diverse payloads activated by radiotherapy. Our findings also suggest that engineering nanoscale surface confinement may provide a generalizable materials strategy to help confer bioorthogonality to otherwise labile activation reactions.
Cellular function depends on the precise deployment and distribution of nanoscale structures, but these features remain difficult to measure and compare between cells and datasets. This challenge is pronounced for astrocytes, whose intricate nanostructures interface with neurons, glia, and vasculature, to control brain development, synaptic development/plasticity, homeostasis, and responses to injury/disease. Here, we developed deep learning approaches with curvature consistency for automated astrocyte segmentation across volume electron microscopy datasets, reducing reconstruction time from manual or semi-automatic methods by 12-fold and enabling brain region and cross-species interrogation of astrocytic nanoarchitecture. This allowed us to uncover organizing principles and motifs alongside ultrastructural divergence between species. While both species exhibit a wide but shallow topological network, marmoset astrocytes display increased process thickness and branching. We further identified extrasynaptic neuronal engulfment and a robust astrocytic endosomal system across species and brain regions. Together, our findings demonstrate previously inaccessible structural principles of astrocytes, offering a framework for understanding structure-function relationships in the central nervous system.
Phase-change perfluorocarbon nanodroplets (PCND) are nanoscale carriers that can be vaporized acoustically to form echogenic microbubbles. This enables ultrasound-triggered imaging and therapy to extend beyond the intravascular space. Despite being extensively studied, their in vivo pharmacokinetics have been reported inconsistently and direct comparisons between formulations are lacking. This limits rational formulation design and translation. Thus, we developed a formulation-property-function framework by systematically decoupling core volatility, shell composition and particle size of protein- and lipid-coated PCND with C5F12 or C6F14 cores and mean diameters of ∼200 and ∼ 300 nm. Across formulations, physicochemical properties, including stability, mechanical deformability and acoustic vaporization threshold, were found to be formulation dependent. These properties, in turn, influence acoustic vaporization, tolerated dose and in vivo pharmacokinetics. Notably, larger or protein-coated PCND exhibited lower acoustic vaporization thresholds, but had lower tolerated doses, shorter circulation half-lives and reduced tumor accumulation. Conversely, smaller or lipid-coated PCND demonstrated improved tolerability, prolonged circulation and greater tumor retention, though they required higher acoustic pressures for vaporization. Additionally, shell mechanics governed PCND deformability, likely influencing their circulation and ability to traverse microvascular constrictions. Tumor accumulation was therefore shaped by both formulation properties and tumor vascular architecture. Formulations with greater stability, deformability, and prolonged circulation accumulated even in less permissive vasculature, whereas formulations with lower stability and shorter circulation required higher vascular permeability for detectable delivery. Overall, we provide a mechanistic framework for PCND design that links formulation parameters to their pharmacological profile and balances vaporization efficiency with in vivo performance and dose tolerability.
Programmable RNA-cleaving DNAzymes (RCDs) represent a unique class of catalytic nucleic acids that couple molecular recognition with enzyme-like activity. While DNAzymes have traditionally been explored for targeted gene regulation, recent advances in nanotechnology have repositioned them as programmable biosensing modules with stimuli-responsive therapeutic potential. When integrated into metal-oxide scaffolds, DNA-framework architectures, or metal-organic frameworks, DNAzymes form hybrid platforms that create confined catalytic microenvironments, provide enriched cofactor availability, and facilitate microenvironment-responsive activation. These engineered systems can function as nanoscale biosensing modules that respond to pH, redox gradients, metal ions, or microRNA signatures and convert these biological cues into catalytic outputs. Beyond enhancing analytical performance, such platforms may also reshape tumor immunometabolism. Through the selective cleavage of metabolic or immune-regulatory transcripts, DNAzyme nanocatalysts can directly reprogram glycolysis, redox balance, oxygen tension, and mitochondrial activity, and these metabolic changes in turn alleviate immunosuppression and promote innate and adaptive immune activation. This review outlines the mechanistic foundations of DNAzyme catalysis, summarizes recent nanoengineering strategies that endow DNAzymes with programmable sensing and stimuli-responsive functions, and discusses how these systems bridge biosensing and catalytic immunometabolic functions. We conclude with perspectives on translational challenges and opportunities, endorsing programmable DNAzyme nanocatalysts as emerging preclinical platforms for biosensing-guided immunometabolic intervention. RNA切割型DNAzyme是一类兼具分子识别能力和酶样催化活性的功能核酸分子，在靶向基因调控、生物传感和肿瘤治疗中具有重要应用潜力。近年来，随着纳米技术的发展，DNAzyme可与金属氧化物、DNA框架结构、金属有机框架等纳米平台集成，形成具有递送保护、金属辅因子供给和肿瘤微环境响应能力的程序化纳米催化体系。这类体系能够响应pH、氧化还原稳态、金属离子和microRNA等内源性信号，并将其转化为特异性RNA催化切割输出。本文系统综述了DNAzyme催化机制、序列与化学工程策略、纳米平台构建方式及其在肿瘤免疫代谢调控中的应用。重点讨论了DNAzyme纳米催化剂如何通过调节糖酵解、氧化还原稳态、线粒体功能、营养竞争及cGAS-STING相关免疫信号，缓解肿瘤免疫抑制并促进抗肿瘤免疫激活。最后，本文总结了该领域在体内递送、辅因子供给、催化特异性、生物安全性和标准化评价方面面临的转化挑战，并展望其作为生物传感引导的肿瘤免疫代谢干预平台的发展前景。.
Extracellular vesicles (EVs) are intercellular mediators in prokaryotic and eukaryotic systems that have the potential to regulate various physiological and pathological processes in recipient cells. Among them, bacterial extracellular vesicles (BEVs), including Gram-negative outer membrane vesicles (OMVs) and Gram-positive membrane vesicles (MVs) produced by the gut microbiota, have special roles in humans and animals. Due to their nanoscale dimensions and distinct molecular payloads, BEVs can cross biological barriers, including the vascular endothelium, to reach distant target tissues and affect various pathophysiological processes. Dysbiosis and compromised epithelial barriers facilitate the systemic dissemination of gut microbiota-derived BEVs, increasing the risk of diseases such as atherosclerosis and cardiovascular disease. Importantly, while this review emphasizes symbiotic intestinal BEVs, evidence from oral and pathogenic bacteria has also been integrated as indirect mechanistic sources to shed more light on BEV-induced endothelial dysfunction and altered angiogenesis. Here, we aimed to highlight the impact of BEVs on the vascular compartment, focusing on endothelial cells (ECs) in terms of molecular and cellular events. Understanding the underlying mechanisms will enable us to develop sophisticated engineered BEVs to control and inhibit certain pathological conditions.
We propose a polarization-engineered displacement sensing scheme that connects the three-dimensional polarization landscape of a tightly focused field with the scattering C-points of an embedded dipolar scatterer. The particle's displacement is encoded as angular shifts of the C-points in the far field. To engineer local polarization states, we first use circularly polarized light to localize the spin-rotating polarization landscape at the focal center, yielding a sensitive, nearly linear evolution of C-points. Furthermore, by employing structured light, we confine the polarization ellipticity variation to the focal center and enable active tuning of displacement sensitivity. Our work demonstrates that engineering of focal-field polarization landscapes via incident light modulation enables tunable high-sensitivity displacement measurement, with potential applications in precision metrology and nanoscale optical sensing.
We report an arc-discharge technique for fabricating surface nanoscale axial photonics (SNAP) microcavities in hollow-core fibers (HCF). Axial compression applied during the discharge counters capillary collapse, allowing sub-nanometer control of the microcavity profile. A coupled physical model couples viscous capillary-flow dynamics with post-cooling refractive-index changes from densification and photoelasticity, mapping both onto the SNAP cutoff wavelength via perturbation theory. With coupling parameters calibrated within their physically plausible ranges, the model reproduces the slope and intercept of the measured apparent-radius response across the full push-velocity range, with quantitative predictions in the collapse regime confirmed by additional low-velocity measurements. These results extend arc-discharge SNAP fabrication into a high-energy regime previously limited by collapse, and provide quantitative predictive control of the microcavity profile for HCF-SNAP devices in microfluidics and photonics.
Chronic infected diabetic foot ulcers (DFUs) pose a persistent challenge due to biofilm-shielded infections, excessive inflammation, and impaired tissue repair. Here, we present a first-in-class microneedle system that redefines eugenol (EUG), a natural compound, as a multifunctional self-assembling material. Beyond its intrinsic therapeutic activity, EUG autonomously forms nanoscale assemblies that penetrate biofilms, suppress inflammation, and act as a natural penetration enhancer. Leveraging these properties, we designed a spatiotemporally controlled microneedle platform integrating dual-phase EUG self-assembly with puerarin (PUE) co-delivery. At the wound surface, EUG assemblies disrupt biofilms and alleviate early inflammation; in deep tissues, their progressive self-assembly sustains antibacterial and anti-inflammatory activity. Meanwhile, EUG facilitates PUE diffusion, while its interaction with the chitosan-based porous matrix ensures gradual release to promote angiogenesis, collagen remodeling, and structured tissue regeneration. Importantly, biodegradable tips detach within 1 h, minimizing secondary trauma. In an infected diabetic rat model, this system halved bacterial burden, reduced interleukin-6 by 60%, accelerated wound closure by 35%, doubled cluster of differentiation 31 expression, and achieved 96.6% ± 4.3% collagen deposition within 14 days, significantly outperforming a commercial silver dressing. This multifunctional, surfactant-free biomaterial platform offers a safe and translational strategy to overcome the "infection-inflammation-healing barrier" in chronic DFUs.
Lipids are fundamental organizers of biological membranes, yet visualizing lipid species within subcellular organelles has remained beyond experimental reach. Lennartz et al. introduce Lipid-correlative light and electron microscopy (CLEM), a CLEM workflow that maps lipid species onto membrane ultrastructure with nanoscale precision, uncovering active sphingomyelin sorting within the early endosome.
DNA origami offers a route to engineering architected metamaterials with sub-nanometer precision by linking nanoscale building blocks into micron-scale assemblies. However, automated design spaces are currently limited to fixed DNA origami motifs, restricting the ability to readily tune a mass-efficient nanostructure stiffness. Here, we introduce a fully automated design paradigm that converts prescribed vertices, edges, and cross-section specifications directly into manufacturable, nucleotide-level models. To demonstrate robustness, three structurally distinct nanostructures are realized under a shared experimental protocol. Further, this paradigm enables the deterministic assembly of hollowframe building blocks into micron-scale architectures, including traditional and auxetic reentrant honeycomb lattices. More broadly, this work establishes a novel design abstraction for stiffness-tunable DNA origami nanostructures that can be rapidly translated into architected metamaterials with distinct functional responses.
The Big Data revolution demands advanced security solutions that are energy-efficient, scalable, and resistant to emerging threats. Conventional encryption, based on algorithmic complexity, is resource-intensive and increasingly vulnerable. To safeguard sensitive information, it is essential to develop innovative anti-hacking and anti-counterfeiting technologies that provide material-level protection embedded at the smallest length scales. Here, we present a selective magneto-ionic strategy for hardware-level security that exploits voltage-controlled N3- ion migration within pre-defined paramagnetic FeCoN dot arrays. This enables the creation of reconfigurable sub-15 nm ferromagnetic sublayers with deterministic or probabilistic (single-domain↔vortex) states and voltage-tunable probabilities. These states facilitate robust magnetic fingerprinting and constitute self-protected primitives suitable for physical unclonable functions and in-memory probabilistic inference, while their stochastic orientation and chirality provide a platform for true random number generation. This architecture combines tamper resistance, low power consumption, and scalability, representing a significant leap toward next-generation hardware security rooted in ion-spin control at the nanoscale.