Bevel-edge epitaxy of ferroelectric rhombohedral boron nitride single crystal.

Within the family of two-dimensional dielectrics, rhombohedral boron nitride (rBN) is considerably promising owing to having not only the superior properties of hexagonal boron nitride1-4-including low permittivity and dissipation, strong electrical insulation, good chemical stability, high thermal conductivity and atomic flatness without dangling bonds-but also useful optical nonlinearity and interfacial ferroelectricity originating from the broken in-plane and out-of-plane centrosymmetry5-23. However, the preparation of large-sized single-crystal rBN layers remains a challenge24-26, owing to the requisite unprecedented growth controls to coordinate the lattice orientation of each layer and the sliding vector of every interface. Here we report a facile methodology using bevel-edge epitaxy to prepare centimetre-sized single-crystal rBN layers with exact interlayer ABC stacking on a vicinal nickel surface. We realized successful accurate fabrication over a single-crystal nickel substrate with bunched step edges of the terrace facet (100) at the bevel facet (110), which simultaneously guided the consistent boron-nitrogen bond orientation in each BN layer and the rhombohedral stacking of BN layers via nucleation near each bevel facet. The pure rhombohedral phase of the as-grown BN layers was verified, and consequently showed robust, homogeneous and switchable ferroelectricity with a high Curie temperature. Our work provides an effective route for accurate stacking-controlled growth of single-crystal two-dimensional layers and presents a foundation for applicable multifunctional devices based on stacked two-dimensional materials.

Graphene nanoribbons grown in hBN stacks for high-performance electronics.

Van der Waals encapsulation of two-dimensional materials in hexagonal boron nitride (hBN) stacks is a promising way to create ultrahigh-performance electronic devices1-4. However, contemporary approaches for achieving van der Waals encapsulation, which involve artificial layer stacking using mechanical transfer techniques, are difficult to control, prone to contamination and unscalable. Here we report the transfer-free direct growth of high-quality graphene nanoribbons (GNRs) in hBN stacks. The as-grown embedded GNRs exhibit highly desirable features being ultralong (up to 0.25 mm), ultranarrow (<5 nm) and homochiral with zigzag edges. Our atomistic simulations show that the mechanism underlying the embedded growth involves ultralow GNR friction when sliding between AA'-stacked hBN layers. Using the grown structures, we demonstrate the transfer-free fabrication of embedded GNR field-effect devices that exhibit excellent performance at room temperature with mobilities of up to 4,600 cm2 V-1 s-1 and on-off ratios of up to 106. This paves the way for the bottom-up fabrication of high-performance electronic devices based on embedded layered materials.

2D fin field-effect transistors integrated with epitaxial high-k gate oxide.

Precise integration of two-dimensional (2D) semiconductors and high-dielectric-constant (k) gate oxides into three-dimensional (3D) vertical-architecture arrays holds promise for developing ultrascaled transistors1-5, but has proved challenging. Here we report the epitaxial synthesis of vertically aligned arrays of 2D fin-oxide heterostructures, a new class of 3D architecture in which high-mobility 2D semiconductor fin Bi2O2Se and single-crystal high-k gate oxide Bi2SeO5 are epitaxially integrated. These 2D fin-oxide epitaxial heterostructures have atomically flat interfaces and ultrathin fin thickness down to one unit cell (1.2 nm), achieving wafer-scale, site-specific and high-density growth of mono-oriented arrays. The as-fabricated 2D fin field-effect transistors (FinFETs) based on Bi2O2Se/Bi2SeO5 epitaxial heterostructures exhibit high electron mobility (µ) up to 270 cm2 V-1 s-1, ultralow off-state current (IOFF) down to about 1 pA µm-1, high on/off current ratios (ION/IOFF) up to 108 and high on-state current (ION) up to 830 µA µm-1 at 400-nm channel length, which meet the low-power specifications projected by the International Roadmap for Devices and Systems (IRDS)6. The 2D fin-oxide epitaxial heterostructures open up new avenues for the further extension of Moore's law.

Epitaxial single-crystal hexagonal boron nitride multilayers on Ni (111).

Large-area single-crystal monolayers of two-dimensional (2D) materials such as graphene1-3, hexagonal boron nitride (hBN)4-6 and transition metal dichalcogenides7,8 have been grown. hBN is considered to be the 'ideal' dielectric for 2D-materials-based field-effect transistors (FETs), offering the potential for extending Moore's law9,10. Although hBN thicker than a monolayer is more desirable as substrate for 2D semiconductors11,12, highly uniform and single-crystal multilayer hBN growth has yet to be demonstrated. Here we report the epitaxial growth of wafer-scale single-crystal trilayer hBN by a chemical vapour deposition (CVD) method. Uniformly aligned hBN islands are found to grow on single-crystal Ni (111) at early stage and finally to coalesce into a single-crystal film. Cross-sectional transmission electron microscopy (TEM) results show that a Ni23B6 interlayer is formed (during cooling) between the single-crystal hBN film and Ni substrate by boron dissolution in Ni. There are epitaxial relationships between hBN and Ni23B6 and between Ni23B6 and Ni. We also find that the hBN film acts as a protective layer that remains intact during catalytic evolution of hydrogen, suggesting continuous single-crystal hBN. This hBN transferred onto the SiO2 (300 nm)/Si wafer acts as a dielectric layer to reduce electron doping from the SiO2 substrate in MoS2 FETs. Our results demonstrate high-quality single-crystal  multilayered hBN over large areas, which should open up new pathways for making it a ubiquitous substrate for 2D semiconductors.

Computational insights into the cross-talk between medin and Aß: implications for age-related vascular risk factors in Alzheimer's disease.

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-ß (Aß) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and Aß results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and Aß-two intrinsically disordered proteins-is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both Aß and medin were aggregation prone and their mixture tended to form ß-sheet-rich hetero-aggregates. The formation of Aß-medin hetero-aggregates did not hinder Aß and medin from recruiting additional Aß and medin peptides to grow into larger ß-sheet-rich aggregates. The ß-barrel oligomer intermediates observed in the self-aggregations of Aß and medin were also present during their co-aggregation. In cross-seeding simulations, preformed Aß fibrils could recruit isolated medin monomers to form elongated ß-sheets. Overall, our comprehensive simulations suggested that the cross-interaction between Aß and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and Aß. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health.

Clonal evolution dissection reveals that a high MSI2 level promotes chemoresistance in T-cell acute lymphoblastic leukemia.

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with resistant clonal propagation in recurrence. We performed high-throughput droplet-based 5' single-cell RNA with paired T-cell receptor (TCR) sequencing of paired diagnosis-relapse (Dx_Rel) T-ALL samples to dissect the clonal diversities. Two leukemic evolutionary patterns, "clonal shift" and "clonal drift" were unveiled. Targeted single-cell DNA sequencing of paired Dx_Rel T-ALL samples further corroborated the existence of the 2 contrasting clonal evolution patterns, revealing that dynamic transcriptional variation might cause the mutationally static clones to evolve chemotherapy resistance. Analysis of commonly enriched drifted gene signatures showed expression of the RNA-binding protein MSI2 was significantly upregulated in the persistent TCR clonotypes at relapse. Integrated in vitro and in vivo functional studies suggested that MSI2 contributed to the proliferation of T-ALL and promoted chemotherapy resistance through the posttranscriptional regulation of MYC, pinpointing MSI2 as an informative biomarker and novel therapeutic target in T-ALL.

Salt stress-induced chloroplastic hydrogen peroxide stimulates pdTPI sulfenylation and methylglyoxal accumulation.

High salinity, an adverse environmental factor affecting about 20% of irrigated arable land worldwide, inhibits plant growth and development by causing oxidative stress, damaging cellular components, and disturbing global metabolism. However, whether and how reactive oxygen species disturb the metabolism of salt-stressed plants remain elusive. Here, we report that salt-induced hydrogen peroxide (H2O2) inhibits the activity of plastid triose phosphate isomerase (pdTPI) to promote methylglyoxal (MG) accumulation and stimulates the sulfenylation of pdTPI at cysteine 74. We also show that MG is a key factor limiting the plant growth, as a decrease in MG levels completely rescued the stunted growth and repressed salt stress tolerance of the pdtpi mutant. Furthermore, targeting CATALASE 2 into chloroplasts to prevent salt-induced overaccumulation of H2O2 conferred salt stress tolerance, revealing a role for chloroplastic H2O2 in salt-caused plant damage. In addition, we demonstrate that the H2O2-mediated accumulation of MG in turn induces H2O2 production, thus forming a regulatory loop that further inhibits the pdTPI activity in salt-stressed plants. Our findings, therefore, illustrate how salt stress induces MG production to inhibit the plant growth.

Seeded growth of large single-crystal copper foils with high-index facets.

The production of large single-crystal metal foils with various facet indices has long been a pursuit in materials science owing to their potential applications in crystal epitaxy, catalysis, electronics and thermal engineering1-5. For a given metal, there are only three sets of low-index facets ({100}, {110} and {111}). In comparison, high-index facets are in principle infinite and could afford richer surface structures and properties. However, the controlled preparation of single-crystal foils with high-index facets is challenging, because they are neither thermodynamically6,7 nor kinetically3 favourable compared to low-index facets6-18. Here we report a seeded growth technique for building a library of single-crystal copper foils with sizes of about 30 × 20 square centimetres and more than 30 kinds of facet. A mild pre-oxidation of polycrystalline copper foils, followed by annealing in a reducing atmosphere, leads to the growth of high-index copper facets that cover almost the entire foil and have the potential of growing to lengths of several metres. The creation of oxide surface layers on our foils means that surface energy minimization is not a key determinant of facet selection for growth, as is usually the case. Instead, facet selection is dictated randomly by the facet of the largest grain (irrespective of its surface energy), which consumes smaller grains and eliminates grain boundaries. Our high-index foils can be used as seeds for the growth of other Cu foils along either the in-plane or the out-of-plane direction. We show that this technique is also applicable to the growth of high-index single-crystal nickel foils, and we explore the possibility of using our high-index copper foils as substrates for the epitaxial growth of two-dimensional materials. Other applications are expected in selective catalysis, low-impedance electrical conduction and heat dissipation.

Seeded growth of single-crystal black phosphorus nanoribbons.

Two-dimensional materials have emerged as an important research frontier for overcoming the challenges in nanoelectronics and for exploring new physics. Among them, black phosphorus, with a combination of a tunable bandgap and high mobility, is one of the most promising systems. In particular, black phosphorus nanoribbons show excellent electrostatic gate control, which can mitigate short-channel effects in nanoscale transistors. Controlled synthesis of black phosphorus nanoribbons, however, has remained an outstanding problem. Here we report large-area growth of black phosphorus nanoribbons directly on insulating substrates. We seed the chemical vapour transport growth with black phosphorus nanoparticles and obtain uniform, single-crystal nanoribbons oriented exclusively along the [100] crystal direction. With comprehensive structural calculations, we discover that self-passivation at the zigzag edges holds the key to the preferential one-dimensional growth. Field-effect transistors based on individual nanoribbons exhibit on/off ratios up to ~104, confirming the good semiconducting behaviour of the nanoribbons. These results demonstrate the potential of black phosphorus nanoribbons for nanoelectronic devices and also provide a platform for investigating the exotic physics in black phosphorus.

Conversion of chirality to twisting via sequential one-dimensional and two-dimensional growth of graphene spirals.

The properties of two-dimensional (2D) van der Waals materials can be tuned through nanostructuring or controlled layer stacking, where interlayer hybridization induces exotic electronic states and transport phenomena. Here we describe a viable approach and underlying mechanism for the assisted self-assembly of twisted layer graphene. The process, which can be implemented in standard chemical vapour deposition growth, is best described by analogy to origami and kirigami with paper. It involves the controlled induction of wrinkle formation in single-layer graphene with subsequent wrinkle folding, tearing and re-growth. Inherent to the process is the formation of intertwined graphene spirals and conversion of the chiral angle of 1D wrinkles into a 2D twist angle of a 3D superlattice. The approach can be extended to other foldable 2D materials and facilitates the production of miniaturized electronic components, including capacitors, resistors, inductors and superconductors.

1T'-transition metal dichalcogenide monolayers stabilized on 4H-Au nanowires for ultrasensitive SERS detection.

Unconventional 1T'-phase transition metal dichalcogenides (TMDs) have aroused tremendous research interest due to their unique phase-dependent physicochemical properties and applications. However, due to the metastable nature of 1T'-TMDs, the controlled synthesis of 1T'-TMD monolayers (MLs) with high phase purity and stability still remains a challenge. Here we report that 4H-Au nanowires (NWs), when used as templates, can induce the quasi-epitaxial growth of high-phase-purity and stable 1T'-TMD MLs, including WS2, WSe2, MoS2 and MoSe2, via a facile and rapid wet-chemical method. The as-synthesized 4H-Au@1T'-TMD core-shell NWs can be used for ultrasensitive surface-enhanced Raman scattering (SERS) detection. For instance, the 4H-Au@1T'-WS2 NWs have achieved attomole-level SERS detections of Rhodamine 6G and a variety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins. This work provides insights into the preparation of high-phase-purity and stable 1T'-TMD MLs on metal substrates or templates, showing great potential in various promising applications.

Epitaxial growth of a 100-square-centimetre single-crystal hexagonal boron nitride monolayer on copper.

The development of two-dimensional (2D) materials has opened up possibilities for their application in electronics, optoelectronics and photovoltaics, because they can provide devices with smaller size, higher speed and additional functionalities compared with conventional silicon-based devices1. The ability to grow large, high-quality single crystals for 2D components-that is, conductors, semiconductors and insulators-is essential for the industrial application of 2D devices2-4. Atom-layered hexagonal boron nitride (hBN), with its excellent stability, flat surface and large bandgap, has been reported to be the best 2D insulator5-12. However, the size of 2D hBN single crystals is typically limited to less than one millimetre13-18, mainly because of difficulties in the growth of such crystals; these include excessive nucleation, which precludes growth from a single nucleus to large single crystals, and the threefold symmetry of the hBN lattice, which leads to antiparallel domains and twin boundaries on most substrates19. Here we report the epitaxial growth of a 100-square-centimetre single-crystal hBN monolayer on a low-symmetry Cu (110) vicinal surface, obtained by annealing an industrial copper foil. Structural characterizations and theoretical calculations indicate that epitaxial growth was achieved by the coupling of Cu <211> step edges with hBN zigzag edges, which breaks the equivalence of antiparallel hBN domains, enabling unidirectional domain alignment better than 99 per cent. The growth kinetics, unidirectional alignment and seamless stitching of the hBN domains are unambiguously demonstrated using centimetre- to atomic-scale characterization techniques. Our findings are expected to facilitate the wide application of 2D devices and lead to the epitaxial growth of broad non-centrosymmetric 2D materials, such as various transition-metal dichalcogenides20-23, to produce large single crystals.

The SOC1 gene plays an important role in regulating litchi flowering time.

Litchi (Litchi chinensis Sonn.) is a valuable subtropical fruit tree with high-quality fruit. However, its economic benefits and sustainable development are restrained by a number of challenges. One major challenge is the lack of extremely early and late maturing high-quality varieties due to limited availability of varieties suitable for commercial cultivation and outdated breeding methods, resulting in an imbalanced supply and low price of litchi. Flowering time is a crucial genetic factor influencing the maturation period of litchi. Our previous research has highlighted the pivotal role of the LcFT1 gene in regulating the flowering time of litchi and identified a gene associated with LcFT1 (named as LcSOC1) based on RNA-Seq and weight gene co-expression network (WGCNA) analysis. This study further investigated the function of LcSOC1. Subcellular localization analysis revealed that LcSOC1 is primarily localized in the nucleus, where it acts as a transcription factor. LcSOC1 overexpression in Nicotiana tabacum and Arabidopsis thaliana resulted in significant early flowering. Furthermore, LcSOC1 was found to be expressed in various tissues, with the highest expression in mature leaves. Analysis of spatial and temporal expression patterns of LcSOC1 in litchi varieties with different flowering time under low temperature treatment and across an annual cycle demonstrated that LcSOC1 is responsive to low temperature induction. Interestingly, early maturing varieties exhibited higher sensitivity to low temperature, with significantly premature induction of LcSOC1 expression relative to late maturing varieties. Activation of LcSOC1 triggered the transition of litchi into the flowering phase. These findings demonstrate that LcSOC1 plays a pivotal role in regulating the flowering process and determining the flowering time in litchi. Overall, this study provides theoretical guidance and important target genes for molecular breeding to regulate litchi production period.

Tip Growth of Quasi-Metallic Bilayer Graphene Nanoribbons with Armchair Chirality.

Graphene nanoribbons (GNRs), quasi one-dimensional (1D) narrow strips of graphene, have shown promise for high-performance nanoelectronics due to their exceptionally high carrier mobility and structurally tunable bandgaps. However, producing chirality-uniform GNRs on insulating substrates remains a big challenge. Here, we report the successful growth of bilayer GNRs with predominantly armchair chirality and ultranarrow widths (<5 nm) on insulating hexagonal boron nitride (h-BN) substrates using chemical vapor deposition (CVD). The growth of GNRs is catalyzed by transition metal nanoparticles, including Fe, Co, and Ni, through a unique tip-growth mechanism. Notably, GNRs catalyzed by Ni exhibit a high purity (97.3%) of armchair chirality. Electron transport measurements indicate that the ultrathin bilayer armchair GNRs exhibit quasi-metallic behavior. This quasi-metallicity is further supported by density functional theory (DFT) calculations, which reveal a significantly reduced bandgap in bilayer armchair GNRs. The chirality-specific GNRs reported here offer promising advancements for the application of graphene in nanoelectronics.

Uncovering the Bronchoalveolar Single-Cell Landscape of Patients With Pulmonary Tuberculosis With Human Immunodeficiency Virus Type 1 Coinfection.

BACKGROUND: Coinfection of human immunodeficiency virus type 1 (HIV-1) is the most significant risk factor for tuberculosis (TB). The immune responses of the lung are essential to restrict the growth of Mycobacterium tuberculosis and avoid the emergence of the disease. Nevertheless, there is still limited knowledge about the local immune response in people with HIV-1-TB coinfection. METHODS: We employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid from 9 individuals with HIV-1-TB coinfection and 10 with pulmonary TB. RESULTS: A total of 19 058 cells were grouped into 4 major cell types: myeloid cells, T/natural killer (NK) cells, B cells, and epithelial cells. The myeloid cells and T/NK cells were further divided into 10 and 11 subsets, respectively. The proportions of dendritic cell subsets, CD4+ T cells, and NK cells were lower in the HIV-1-TB coinfection group compared to the TB group, while the frequency of CD8+ T cells was higher. Additionally, we identified numerous differentially expressed genes between the CD4+ and CD8+ T-cell subsets between the 2 groups. CONCLUSIONS: HIV-1 infection not only affects the abundance of immune cells in the lungs but also alters their functions in patients with pulmonary TB.

Chronic kidney disease in a murine model of non-alcoholic steatohepatitis (NASH).

Clinical studies suggest that non-alcoholic steatohepatitis (NASH) is an independent risk factor for chronic kidney disease (CKD), but causality and mechanisms linking these two major diseases are lacking. To assess whether NASH can induce CKD, we have characterized kidney function, histological features, transcriptomic and lipidomic profiles in a well-validated murine NASH model. Mice with NASH progressively developed significant podocyte foot process effacement, proteinuria, glomerulosclerosis, tubular epithelial cell injury, lipid accumulation, and interstitial fibrosis. The progression of kidney fibrosis paralleled the severity of the histologic NASH-activity score. Significantly, we confirmed the causal link between NASH and CKD by orthotopic liver transplantation, which attenuated proteinuria, kidney dysfunction, and fibrosis compared with control sham operated mice. Transcriptomic analysis of mouse kidney cortices revealed differentially expressed genes that were highly enriched in mitochondrial dysfunction, lipid metabolic process, and insulin signaling pathways in NASH-induced CKD. Lipidomic analysis of kidney cortices further revealed that phospholipids and sphingolipids were the most significantly changed lipid species. Notably, we found similar kidney histological changes in human NASH and CKD. Thus, our results confirm a causative role of NASH in the development of CKD, reveal potential pathophysiologic mechanisms of NASH-induced kidney injury, and established a valuable model to study the pathogenesis of NASH-associated CKD. This is an important feature of fatty liver disease that has been largely overlooked but has clinical and prognostic importance.

Nanoplastic Stimulates the Amyloidogenesis of Parkinson's Alpha-Synuclein NACore.

Environmental plastic wastes are potential health hazards due to their prevalence as well as their versatility in initiating physical, chemical, and biological interactions and transformations. Indeed, recent research has implicated the adverse effects of micro- and nano-plastics, including their neurotoxicity, yet how plastic particulates may impact the aggregation pathway and toxicity of amyloid proteins pertinent to the pathologies of neurological diseases remains unknown. Here, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) is employed to reveal the polymorphic oligomerization of NACore, a surrogate of alpha-synuclein that is associated with the pathogenesis of Parkinson's disease. These data indicate that the production rate and population of the NACore oligomers are modulated by their exposure to a polystyrene nanoplastic, and these cellular assays further reveal an elevated NACore toxicity in microglial cells elicited by the nanoplastic. These simulations confirm that the nanoplastic-NACore association is promoted by their hydrophobic interactions. These findings are corroborated by an impairment in zebrafish hatching, survival, and development in vivo upon their embryonic exposure to the nanoplastic. Together, this study has uncovered the dynamics and mechanism of amyloidogenesis elevated by a nanoplastic trigger, shedding a new light on the neurological burden of plastic pollution.

Double-Phase-Networking Polyimide Hybrid Aerogel with Exceptional Dimensional Stability for Superior Thermal Protection System.

Polyimide aerogels have been extensively used in thermal protection domain because they possess a combination of intrinsic characteristics of aerogels and unique features of polyimide. However, polyimide aerogels still suffer significant thermally induced shrinkage at temperatures above 200 °C, restricting their application at high temperature. Here, a novel "double-phase-networking" strategy is proposed for fabricating a lightweight and mechanically robust polyimide hybrid aerogel by forming silica-zirconia-phase networking skeletons, which possess exceptional dimensional stability in high-temperature environments and superior thermal insulation. The rational mechanism responsible for the formation of double-phase-networking aerogel is further explained, generally attributing to chemical crosslinking reactions and supramolecular hydrogen bond interactions derived from the main chains of polyimide and silane/zirconia precursor/sol. The as-prepared aerogels exhibit excellent high-temperature (270 °C) dimensional stability (5.09% ± 0.16%), anti-thermal-shock properties, and low thermal conductivity. Moreover, the hydrophobic treatment provides aerogels high water resistance with water contact angle of 136.9°, further suggestive of low moisture content of 3.6% after exposure to 70 °C and 85% relative humidity for 64 h. The proposed solution for significantly enhancing high-temperature dimensional stability and thermal insulation provides a great supporting foundation for fabricating high-performance organic aerogels as thermal protection materials in aerospace.

The Reconstruction of Pt(001) Surface and the Shell-Like Reconstruction of the Vicinal Pt(001) Surfaces Revealed by Neural Network Potential.

In this work, a highly accurate neural network potential (NNP) is presented, named PtNNP, and the exploration of the reconstruction of the Pt(001) surface and its vicinal surfaces with it. Contrary to the most accepted understanding of the Pt(001) surface reconstruction, the study reveals that the main driving force behind Pt(001) quasi-hexagonal reconstruction is not the surface stress relaxation but the increased coordination number of the surface atoms resulting in stronger intralayer binding in the reconstructed surface layer. In agreement with experimental observations, the optimized supercell size of the reconstructed Pt(001) surface contains (5 × 20) unit cells. Surprisingly, the reconstruction of the vicinal Pt(001) surfaces leads to a smooth shell-like surface layer covering the whole surface and diminishing sharp step edges.

Advancing targeted combination chemotherapy in triple negative breast cancer: nucleolin aptamer-mediated controlled drug release.

BACKGROUND: Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. METHODS: We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. RESULTS: Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. CONCLUSIONS: This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.