β-Strand motifs are essential recognition modules in protein-protein interactions (PPIs), which govern cellular signaling networks and regulate molecular pathway dynamics. Herein we present an unexpected discovery of a previously uncharacterized β-strand insertion mechanism termed as cross-β-strand linking, wherein β-strands within the β-sheet-rich aggregates form inter-β-sheet connections through insertion into adjacent β-sheets. These cross-β-strand linkers comprise <15

Cancer metastasis presents a formidable clinical challenge, demanding innovative therapeutic approaches. Compared to normal cells, the enhanced migratory capacity of malignant cancer cells plays a pivotal role in the metastatic process. Targeting this differential motility to inhibit migration may offer a novel strategy for cancer treatment. We found that the piezoionic hydrogels significantly inhibited the migration of human hepatocellular carcinoma cells (Huh-7) which are characterized by high migratory capacity, with minimal impact on normal cell migration. Cell adhesion genes like ICAM1 increased and N-cadherin decreased on the piezoionic hydrogel. Besides, piezoionic hydrogels induced calcium overload in cancer cells by activating Piezo1 and promoting excessive calcium influx, which can disrupt mitochondrial function and compromise cytoskeletal integrity, ultimately hindering cell migration. Crucially, our research has pioneered the validation of a novel strategy: harnessing the inherent migratory properties of cancer cells to suppress their own migration, while exerting minimal inhibitory effects on normal cells with weaker migratory capabilities, may offer a superior method and strategy for specifically targeting and inhibiting malignant cancer cell metastasis.

Abstract Three copper(I) iodide coordination polymers (CPs), Cu2I2(bpp)(PPh3)2 (1, bpp = 1,3-dipyridylpropane, PPh3 = triphenylphosphine), Cu2I2(bpp)(PPh2(Tol))2 (2, PPh2(Tol) = diphenyl-p-tolylphosphine), and Cu2I2(bpp)(P(Tol)3)2 (3, P(Tol)3 = tri-p-tolylphosphine), were synthesized from 1,3-dipyridylpropane as the bridging ligand and triphenylphosphine and its methyl-substituted derivatives as terminal ligands for high-performance X-ray scintillation. Single-crystal X-ray diffraction analysis revealed that monomethyl substitution in CP 2 maintains isostructural chain connectivity with CP 1, but significantly enhances the compactness of molecular packing. Further increasing methyl substituents led to distinct chain connectivity in CP 3. All three CPs exhibited room-temperature thermally activated delayed fluorescence with high photoluminescence quantum yields of 91%, 99%, and 88% for 1, 2, and 3. Benefiting from the strong X-ray absorption of heavy Cu and I atoms and high luminescence efficiency, all three CPs show outstanding X-ray scintillation performance, with XEL intensities 5.4, 7.6, and 5.9 times that of the commercial BGO scintillator, respectively. The optimal CP 2 exhibits a low detection limit of 20.4 nGy/s and a high spatial resolution of 20 lp mm–1 in X-ray imaging, demonstrating its great potential application in X-ray imaging. This work provides a facile ligand engineering strategy to regulate the crystal structure and packing of copper(I) iodide CPs, offering valuable design insights for developing high-performance scintillation materials.

Background/Objectives: Lipid nanoparticles (LNPs) have emerged as crucial vehicles for messenger RNA (mRNA) applications in antitumor therapy. Combining LNPs with stimulator of interferon genes (STING) activation holds promise for treating “cold” tumors such as pancreatic cancer. However, two major challenges remain: inefficient mRNA escape from endosomes and STING pathway suppression in immunosuppressive tumor microenvironments. Methods: To improve endosomal escape, we developed a novel pH-responsive PEGylated lipid (Ben-mPEG2000) for mRNA-LNP preparation while using commercial Man-mPEG2000 for dendritic cell (DC)-targeted delivery of LNPs; to alleviate suppression of the STING pathway in the tumor microenvironment and activate immune responses, STING-R283S mRNA was encapsulated into LNPs, ultimately resulting in DC-targeted/pH-responsive LNPs loaded with STING-R283S mRNA for pancreatic cancer immunotherapy research. Results: After pH-responsive cleavage, Ben-mPEG2000 not only enhanced the positive charge of LNPs through the exposed protonated amino groups but also eliminated the PEG-induced steric hindrance effect. The combination of these two effects promoted membrane fusion between LNPs and the endosome, thereby enhancing mRNA translation. As a payload, STING-R283S could further amplify STING signaling in DCs without cytotoxicity to counteract immunosuppression in pancreatic cancer. Conclusions: This engineered LNP platform enhanced mRNA expression and STING activation in DCs, improving immunotherapy outcomes in pancreatic cancer.

Liver metastasis is a major factor contributing to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). The formation of pre-metastatic niche (PMN) initiates the process of liver metastasis. Exosomes (Exos) act as key mediators of crosstalk between the tumor microenvironment (TME) and the PMN to activate hepatic stellate cells (HSCs) and remodel the stiff extracellular matrix (ECM). In this study, we isolated Exos derived from PDAC cells cultured under acidic conditions and demonstrated that these Exos significantly activate HSCs and promote the remodeling of the stiff ECM, thereby promoting the stemness, migration, and invasion of PDAC cells. High expression of exosomal miR-1246 was screened by miRNA-sequencing, and Wiskott-Aldrich syndrome protein Family Member 3 (WASF3) was identified as the target of miR-1246. Mechanistically, exosomal miR-1246 activates HSCs to remodel the ECM by targeting WASF3 and stimulating the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K/Akt) pathway. Notably, RNA-binding protein immunoprecipitation (RIP) and miRNA pull-down assays were performed to identify that Human Antigen R (HuR) contributes to the enrichment of miR-1246 into Exos. Collectively, exosomal miR-1246 activates HSCs and remodels the stiff ECM to promote liver metastasis, and it may serve as a potential diagnostic and prognostic marker for PDAC liver metastasis.

Optoelectronic synaptic devices, which integrate optical sensing and synaptic plasticity, are pivotal for emulating biological visual systems and advancing neuromorphic computing. Herein, we report versatile optoelectronic synapses based on SnO2/titanicone (Ti-based hydroquinone, Ti-HQ) heterojunctions fabricated via atomic/molecular layer deposition (ALD/MLD). The SnO2/Ti-HQ heterojunction structure introduces abundant charge trapping sites and a built-in electric field, significantly enhancing the optoelectronic response and relaxation time compared to a single inorganic SnO2 device. Importantly, this ALD/MLD-enabled optoelectronic heterojunction strategy exhibits general applicability and can be successfully extended to other metal oxide/metalcone systems. The SnO2/Ti-HQ device emulates a variety of synaptic behaviors, including excitatory postsynaptic current (EPSC), paired-pulse facilitation (PPF), transition from short-term plasticity (STP) to long-term plasticity (LTP), and the learning-forgetting-relearning process. The extremely low energy consumption per spike is confirmed in this device with ∼1.13 fJ at 0.1 mV ultralow bias voltage. Notably, the hybrid device also exhibits exceptional air stability, retaining 90% of initial EPSC after ambient storage for 9 months. Furthermore, optical logic operations and image preprocessing capabilities have been realized in the hybrid heterojunction devices. Its wavelength-dependent responses from ultraviolet to red light enable color discrimination. A proof-of-concept intelligent vehicle system, controlled by light wavelength, validates its potential for artificial vision. This work highlights a feasible and effective route for artificial optoelectronic synapses based on inorganic-organic hybrid heterojunctions by powerful ALD/MLD technology, showing enormous potentials in energy-efficient neuromorphic devices for multifunctional applications, especially in the biomimetic visual system.

Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) are regarded as important "cellfree" therapeutic carriers due to their potential for immune regulation and tissue repair. However, their largescale application is constrained by bottlenecks such as low secretion yields under conventional culture conditions. This study established a magnetically controlled dynamic mechanical stimulation platform to enhance MSC-sEVs production. Superparamagnetic Fe3O4 nanoparticles were embedded into polyacrylamide to form magnetic composite hydrogels. An variable magnetic field induced reversible deformation of the hydrogel, thereby applying periodic mechanical loading to adherent cells. Results demonstrate that, compared to conventional plastic substrates, dynamic loading on MSCs significantly increases sEVs secretion (up to approximately 5-fold) without altering typical vesicle morphology or size distribution. Mechanistic studies indicate that this stimulus induces upregulation of the mechanosensitive channel Piezo1 and the nuclear YAP signaling pathway, thereby promoting sEVs release. Inhibition of Piezo1 or YAP attenuated the enhanced production effect, supporting a dual-pathway synergistic model where "Piezo1-Ca2+ promotes release, while YAP promotes multivesicular bodies (MVB) generation." This platform offers an economical, simple, and promising solution for efficient and controllable sEVs production.

Dentin regeneration remains a key clinical challenge due to the lack of bioactive materials capable of dynamically regulating the native microenvironment. A multifunctional piezoelectric scaffold that integrates mechanical reinforcement, piezoelectric stimulation, bioactive ion release, biomineralization, and antibacterial activity is developed by embedding strontium-polyoxometalate (Sr-POM) subnanowires (SNWs) into a poly(vinylidene fluoride) (PVDF) matrix. Sr-POM SNWs incorporation enhances PVDF’s piezoelectric β-phase content by 67.54%, boosting piezoelectric output voltage by ∼2900%, and reinforcing the piezoelectric scaffold (68.83% tensile strength and 198% toughness increases). The scaffold generates local electrical potentials under mechanical stimulation to promote intracellular Ca2 + influx, sustainably releases Sr2+ to promote odontogenic differentiation of human dental pulp stem cells, and PW12O403- to guide hydroxyapatite mineralization, with enhanced piezoelectricity disrupting bacterial membranes. In vitro, the piezoelectric scaffold promotes cell adhesion, differentiation, and mineralization, while in vivo it exhibits good biosafety, upregulates dentin sialophosphoprotein expression and induces dentin regeneration in a rat pulp-capping model. This integrated strategy couples biophysical and biochemical cues, offering a promising platform for functional dentin repair.

Abstract Gemcitabine (GEM) is a first-line therapeutic option for pancreatic cancer; however, it has low efficacy due to rapidly developed drug resistance and severe dose-limiting myelosuppression. To enhance its therapeutic effect, this study developed a novel peptide−drug conjugate using a CXCR4 antagonistic peptide as the targeting head and gemcitabine as the drug payload, based on the characteristics of pancreatic tumor cells highly expressing CXCR4 that mediates immunosuppression and tumor progression through interaction with its specific ligand CXCL12. The therapeutic effect of the conjugate (P12-GEM) was investigated using pancreatic ductal adenocarcinoma cell lines and an orthotopic pancreatic cancer mouse model. Its myelosuppressive effect was assessed from the perspective of hematological toxicity profiles. The results showed that P12-GEM maintained a cell-killing capability comparable to that of GEM while effectively inhibiting the phosphorylation of Erk and P38, thereby reducing CXCL12-mediated tumor cell migration and adhesion to stromal cells. In a tumor-bearing mouse model, P12-GEM demonstrated superior antitumor efficacy compared to GEM and significantly extended animal survival. Moreover, P12-GEM reduced the proportion of tumor-associated macrophages and increased the infiltration of CD8+ T cells in the tumor microenvironment without reducing platelet and white blood cell counts in the peripheral blood. In summary, P12-GEM possesses dual functions of CXCR4 antagonism and tumor cell killing, contributing to reversal of the immunosuppressive microenvironment and alleviation of myelotoxicity.

The spontaneous crystallization of galectin-10 (gal-10) in vivo is closely associated with the pathological mechanisms of certain intractable diseases, including eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP), for which targeted therapies are currently lacking. Gal-10 crystals have been identified as a promising target for clinical intervention against these diseases. However, the development of small-molecule drugs that target gal-10 crystallization has remained elusive. In this study, we discover an FDA-approved drug, metformin, which effectively induces the dissociation of gal-10 crystals in vitro by exploiting ion-specific effects that modulate the stability of protein crystals. We assess the therapeutic efficacy of metformin through both intratracheal and oral administration in a mouse model with gal-10 crystal-induced lung inflammation. Our results, including proinflammatory cytokine release and pathology tests, highlight the potency of metformin in ameliorating the symptoms of gal-10 crystallopathy in vivo. This work demonstrates a drug repurposing strategy that can guide the discovery of lead compounds for the treatment of protein crystallopathies.

Prokaryotic Argonaute (pAgo) proteins constitute an evolutionarily ancient nuclease family that is rapidly maturing into a versatile molecular toolkit rivaling CRISPR-Cas. This review synthesizes recent advances in pAgo biology and biotechnology, tracing their phylogeny across thermophilic, mesophilic, and psychrotolerant lineages and highlighting temperature-adapted catalytic signatures that diverge from eukaryotic Agos. In vivo studies reveal pAgo roles in gDNA-guided host defense, transcriptional silencing and recombination, all executed through programmable DNA- or RNA-guided nuclease activity. We detail how guide length, 5' nucleotide identity, divalent cations and accessory factors modulate cleavage efficiency, enabling rational optimization. The review then maps the explosion of pAgo-based biosensing platforms, including selective nucleic acid enrichment platforms, ultrasensitive pathogen detection methods, programmable DNA cloning systems, and high-resolution imaging techniques. Their independence from protospacer adjacent motifs (PAMs), stable DNA guides, multi-turnover kinetics, and broad thermal tolerance position pAgos as ideal complements to CRISPR systems. Finally, we outline current limitations and future directions, including the discovery and engineering of novel variants, elucidation of guide-generation mechanisms, and development of next-generation gene-editing tools, aiming to accelerate translation of these versatile enzymes into practical biotechnological and therapeutic translation.

Ischemic stroke (IS) triggers neuroinflammatory cascades mediated by microglial polarization, where pro-inflammatory M1 phenotypes exacerbate neuronal damage and anti-inflammatory M2 phenotypes promote repair. Edaravone (Eda), a free radical scavenger, shows potential for modulating microglial polarization but faces challenges in penetrating the blood-brain barrier (BBB) and achieving targeted delivery. This study develops a hybrid nanoparticle (SHp-NSCsome) that integrates hypoxia-preconditioned neural stem cell-derived exosomes with Eda-loaded liposomes functionalized with the ischemic-homing peptide SHp. SHp-NSCsome combines the biocompatibility and immunomodulatory properties of exosomes with the drug-loading capacity of liposomes, enabling efficient BBB traversal and targeting of ischemic lesions. In vitro analyses demonstrated the superior anti-apoptotic effects, mitochondrial protection, and M2 polarization of microglia by SHp-NSCs under oxygen-glucose deprivation, significantly reducing pro-inflammatory cytokines while enhancing anti-inflammatory mediators. In vivo studies involving mice subjected to middle cerebral artery occlusion (MCAO) indicated a significant accumulation of SHp-NSCsome within ischemic areas, leading to a decrease in infarct size and improvement in neurological function. Mechanistically, SHp-NSCsome regulates microglial polarization by inhibiting the glycolysis pathway mediated by HIF-1α. These dual-functional nanoparticles synergize antioxidant and immunoregulatory actions, offering a promising therapeutic strategy for IS by precisely modulating post-ischemic neuroinflammation.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Although an immune checkpoint blockade can reduce metastasis, its effectiveness is hindered by the immunosuppressive microenvironment in TNBC. EZH2 is overexpressed in TNBC, and patients with high EZH2 expression are associated with poor prognoses. The study developed EIP103 as a first-in-class peptide degrader that targets EZH2 through multivalent, high-affinity interactions and induces conformational destabilization, representing a mechanism distinct from that of the small molecule inhibitor EPZ-6438. The results demonstrated that EIP103 induces immunogenic cell death through lipid peroxidation, resulting in enhanced immune cell infiltration. Additionally, molecular dynamics (MD) simulations and biochemical assays revealed that the peptide EIP103 binds to the SET domain of EZH2, altering its structure and triggering proteasomal degradation via Praja Ring Finger Ubiquitin Ligase 2 (PJA2)-mediated ubiquitination. Harboring both enzymatic inhibition and post-translational regulation properties, EIP103 exerts durable efficacy and activates antitumor immunity, making it a promising therapeutic candidate for TNBC.

Nanotechnology-based drug delivery systems (NDDSs) represent a promising paradigm for cancer therapy. Nonetheless, their clinical translation is substantially impeded by the heterogeneous and physiologically complex tumor microenvironment-particularly the limited penetration of therapeutic agents into the deeper stromal and parenchymal compartments of solid tumors-constituting a critical barrier that warrants urgent scientific investigation. We developed a size-transformable nanomicelle drug delivery system (PCAmDM) utilizing amphiphilic dendrimers and PEGylated polymers, employing a modular co-assembly strategy with in situ bioorthogonal chemistry. The PCAmDM nanomicelles achieved a high doxorubicin (DOX) loading efficiency, featuring a PEGylated surface that enhances stability, prolongs blood circulation, and promotes tumor accumulation via the enhanced permeability and retention (EPR) effect. These nanomicelles exhibit pH-responsive size reduction in the acidic tumor microenvironment (TME), releasing smaller nanomicelles to enhance penetration and therapeutic efficacy in various tumor multicellular spheroids. The size-transformable PCAmDM significantly enhances the in vivo therapeutic efficacy of DOX while reducing systemic toxicity in pancreatic xenograft models. These results highlight the significant potential of this TME-responsive, dendrimer-based nanoplatform as a next-generation drug delivery system in precision cancer therapy. Furthermore, it offers a broadly applicable strategy to enhance the clinical use of traditional chemotherapeutics and provides a versatile framework for designing smart nanocarriers with tailored properties for advanced oncology applications. STATEMENT OF SIGNIFICANCE: Nanotechnology-enabled drug delivery systems offer significant therapeutic potential for cancer treatment. However, the effectiveness of current methods is often limited by the heterogeneous tumor microenvironment, especially the poor penetration of therapeutics into deeper tumor regions. To address this key challenge, we developed size-transformable nanomicelles from amphiphilic dendrimers through modular co-assembly and in situ bioorthogonal chemistry. These engineered nanomicelles demonstrate superior features, including high drug loading, prolonged circulation, increased tumor accumulation, and notably, better penetration into deep tumor tissues. As a result, they achieved remarkable therapeutic results in pancreatic xenograft models. This work provides new insights into designing dendrimer-based nanomicelles as a promising platform for deep tumor-penetrating drug delivery in precision cancer therapy.

Extracellular vesicles (EVs) are promising drug-delivery vehicles owing to their biocompatibility and low immunogenicity. Genetic engineering of a membrane-bound EV-sorting scaffold protein empowers EVs by installing targeting moieties on the surface and enriching therapeutic cargo in the lumen. However, the choice of scaffold proteins with simple structures and short sequences is limited. Here, we conduct mass spectrometry-based proteomic studies and identify ENPP1 as a superior scaffold protein. Furthermore, we show that a truncated 144-amino acid variant, EN144, efficiently loads diverse therapeutic cargoes and outperforms conventional scaffolds. By fusing EN144 to the IL-6 decoy receptor gp130, we create engineered decoy EVs that potently inhibit inflammatory IL-6 trans-signaling. In mouse models, these EVs reduce inflammation, improve survival in sepsis, and, when targeted to cartilage, alleviate tissue damage in osteoarthritis. Our work establishes EN144 as a minimal, high-performance scaffold for EV engineering and demonstrates its broad therapeutic potential for inflammatory diseases.

With the continuous shrinkage of feature sizes in integrated circuits, the challenges faced by copper interconnects are becoming increasingly severe. Traditional Ta/TaN laminated barrier layers can no longer meet the requirements of advanced process nodes, making it urgent to develop new and efficient barrier materials.A green and facile electrochemical method was employed to in-situ prepare reduced graphene oxide (rGO) films on heavily doped silicon substrates, which were used as a new type of barrier layer for copper interconnections. The as-prepared films were systematically characterized by scanning electron microscopy (SEM), Raman spectroscopy and energy-dispersive X-ray spectroscopy (EDS).The thin film prepared through process optimization has a dense and uniform structure, strong adhesion to the substrate, and excellent electrical conductivity. After high-temperature annealing treatment, the film can still block the elemental diffusion between copper and silicon while maintaining a low interfacial contact resistance.The new approach proposed in this study can be referenced for the design of low-resistance and high-reliability barrier layers used in next-generation advanced interconnect structures.

The aggregation kinetics of alpha-synuclein (alpha-syn) is closely related to the disease progression of Parkinson's disease (PD). The structural dynamics of the alpha-syn aggregation process and the effects of post-translational modifications on its aggregation are very crucial while have not been elucidated. In this study, structural evolution and aggregation kinetics of the wild-type non-amyloid-(3 component (NAC) and Serine 87 site phosphorylation mutant (pNAC) of alpha-syn were monitored in situ by using fast scanning atomic force microscopy (AFM) in real time. The impact of phosphorylation on the aggregation behaviors was demonstrated by time-lapse AFM images. Phosphorylation at Ser87 reduced the intrinsic homotypic aggregation rate of the NAC fragment, and disrupted the regular helical structure of the original fibrils. Nevertheless, preformed pNAC fibrils act as potent cross-seeding templates that accelerate the aggregation of unmodified NAC monomers via the heterogeneous nucleation mechanism. Molecular dynamics simulation revealed that pNAC monomers tend to form more stable conformations, making it difficult to initiate nucleation, and the formed pNAC fibrils also exhibit higher instability. We proposed the mechanisms of phosphorylation effects on amyloid nucleation and aggregation, which will shed light on the pathological protein aggregation, and the development of strategies to prevent or treat neurodegenerative diseases.

Antimicrobial agents with favourable food safety profiles are urgently needed to control human pathogenic bacteria associated with aquatic products. A mass spectrometry- and bioassay-guided screening approach was employed to identify structurally novel peptide natural products with potential as food-safe antimicrobial agents. This effort led to the discovery of eight new antibacterial 11-mer peptaibols, sesquicilins A–H (1–8), from the ascomycete fungus Sesquicilium sp. QL0466. Their planar structures were elucidated by integrated analysis of HRESIMS/MS and NMR spectroscopic data, and the absolute configurations of the chiral amino acids were established using the advanced Marfey's method. These compounds feature characteristic Ser2 and Iva8-Gln9-Aib/Iva/Leu10 motifs, setting them apart from previously reported 11-mer peptaibols. Bioinformatic analysis revealed a nonribosomal peptide synthetase gene cluster likely responsible for sesquicilin biosynthesis. Among these peptaibols, compound 2 potently inhibited the growth of Staphylococcus and Salmonella species, while showing no detectable activity against common aquaculture pathogenic bacteria. This selective antibacterial profile minimizes the risk of misuse in aquaculture and the consequent rapid emergence of antimicrobial resistance. Structure-activity relationship analysis indicated the critical role of d-isovaline residue at the 1st position in mediating antibacterial activity.