WWTR1(TAZ)-CAMTA1 gene fusion is sufficient to dysregulate YAP/TAZ signaling and drive epithelioid hemangioendothelioma tumorigenesis.

Epithelioid hemangioendothelioma (EHE) is a genetically homogenous vascular sarcoma that is a paradigm for TAZ dysregulation in cancer. EHE harbors a WWTR1(TAZ)-CAMTA1 gene fusion in >90% of cases, 45% of which have no other genetic alterations. In this study, we used a first of its kind approach to target the Wwtr1-Camta1 gene fusion to the Wwtr1 locus, to develop a conditional EHE mouse model whereby Wwtr1-Camta1 is controlled by the endogenous transcriptional regulators upon Cre activation. These mice develop EHE tumors that are indistinguishable from human EHE clinically, histologically, immunohistochemically, and genetically. Overall, these results demonstrate unequivocally that TAZ-CAMTA1 is sufficient to drive EHE formation with exquisite specificity, as no other tumor types were observed. Furthermore, we fully credential this unique EHE mouse model as a valid preclinical model for understanding the role of TAZ dysregulation in cancer formation and for testing therapies directed at TAZ-CAMTA1, TAZ, and YAP/TAZ signaling.

Epithelioid hemangioendothelioma (EHE) with WWTR1::TFE3 gene fusion, a novel fusion variant.

Epithelioid hemangioendothelioma (EHE) is a rare endothelial sarcoma associated with a high incidence of metastases and for which there are no standard treatment options. Based on disease-defining mutations, most EHEs are classified into two subtypes: WWTR1::CAMTA1-fused EHE or YAP1::TFE3-fused EHE. However, rare non-canonical fusions have been identified in clinical samples of EHE cases and are challenging to classify. In this study, we report the identification of a novel WWTR1::TFE3 fusion variant in an EHE patient using targeted RNA sequencing. Histologically, the tumor exhibited hybrid morphological characteristics between WWTR1::CAMTA1-fused EHE and YAP1::TFE3-fused EHE. In addition to the driver fusion, there were six additional secondary mutations identified, including a loss-of-function FANCA mutation. Furthermore, in vitro studies were conducted to investigate the tumorigenic function of the WWTR1::TFE3 fusion protein in NIH3T3 cells and demonstrated that WWTR1::TFE3 promotes colony formation in soft agar. Finally, as the wild-type WWTR1 protein relies on binding the TEAD family of transcription factors to affect gene transcription, mutation of the WWTR1 domain of the fusion protein to inhibit such binding abrogates the transformative effect of WWTR1::TFE3. Overall, we describe a novel gene fusion in EHE with a hybrid histological appearance between the two major genetic subtypes of EHE. Further cases of this very rare subtype of EHE will need to be identified to fully elucidate the clinical and pathological characteristics of this unusual subtype of EHE.

The cilia and flagella associated protein CFAP52 orchestrated with CFAP45 is required for sperm motility in mice.

Asthenozoospermia characterized by decreased sperm motility is a major cause of male infertility, but the majority of the etiology remains unknown. Here, we showed that the cilia and flagella associated protein 52 (Cfap52) gene was predominantly expressed in testis and its deletion in a Cfap52 knockout mouse model resulted in decreased sperm motility and male infertility. Cfap52 knockout also led to the disorganization of the midpiece-principal piece junction of the sperm tail but had no effect on the axoneme ultrastructure in spermatozoa. Furthermore, we found that CFAP52 interacted with the cilia and flagella associated protein 45 (CFAP45) and knockout of Cfap52 decreased the expression level of CFAP45 in sperm flagellum, which further disrupted the microtubule sliding produced by dynein ATPase. Together, our studies demonstrate that CFAP52 plays an essential role in sperm motility by interacting with CFAP45 in sperm flagellum, providing insights into the potential pathogenesis of the infertility of the human CFAP52 mutations.

Inferred drought-induced plant allocation shifts and their impact on drought legacy at a tropical forest site.

While droughts predominantly induce immediate reductions in plant carbon uptake, they can also exert long-lasting effects on carbon fluxes through associated changes in leaf area, soil carbon, etc. Among other mechanisms, shifts in carbon allocation due to water stress can contribute to the legacy effects of drought on carbon fluxes. However, the magnitude and impact of these allocation shifts on carbon fluxes and pools remain poorly understood. Using data from a wet tropical flux tower site in French Guiana, we demonstrate that drought-induced carbon allocation shifts can be reliably inferred by assimilating Net Biosphere Exchange (NBE) and other observations within the CARbon DAta MOdel fraMework. This model-data fusion system allows inference of optimized carbon and water cycle parameters and states from multiple observational data streams. We then examined how these inferred shifts affected the duration and magnitude of drought's impact on NBE during and after the extreme event. Compared to a static allocation scheme analogous to those typically implemented in land surface models, dynamic allocation reduced average carbon uptake during drought recovery by a factor of 2.8. Additionally, the dynamic model extended the average recovery time by 5 months. The inferred allocation shifts influenced the post-drought period by altering foliage and fine root pools, which in turn modulated gross primary productivity and heterotrophic respiration for up to a decade. These changes can create a bust-boom cycle where carbon uptake is enhanced some years after a drought, compared to what would have occurred under drought-free conditions. Overall, allocation shifts accounted for 65% [45%-75%] of drought legacy effects in modeled NBE. In summary, drought-induced carbon allocation shifts can play a substantial role in the enduring influence of drought on cumulative land-atmosphere CO2 exchanges and should be accounted for in ecosystem models.

Bioaccessibility and bioavailability of exogenous and endogenous toxic substances in traditional Chinese medicine and their significance in risk assessment.

Scientific risk assessment of exogenous and endogenous toxic substances in traditional Chinese medicine (TCM) is of great significance. The present review comprises a comprehensive summary of progress in the health risk assessment of harmful exogenous substances in TCMs. Such substances include heavy metals, pesticide residues, biotoxins, and endogenous toxic components involving pyrrolizidine alkaloids. The review also discusses the strengths and weaknesses of various bioaccessibility and bioavailability models, and their applications in risk assessment. Future avenues of risk assessment research are highlighted, including further exploration of risk assessment parameters, innovation of bioaccessibility and bioavailability techniques, enhancement of probabilistic risk assessment combined with bioavailability, improvement of cumulative risk assessment strategies, and formulation of strategies for reducing relative bioavailability (RBA) values in TCMs. Such efforts represent an attempt to develop a risk assessment system that is capable of evaluating the exogenous and endogenous toxic substances in TCMs to ensure its safe use in clinics, and to promote the sustainable development of the TCM industry.

Vitamin D supplementation for cardiometabolic risk markers in pregnant women based on the gestational diabetes mellitus or obesity status : a randomized clinical trial.

PURPOSE: Women with gestational diabetes mellitus (GDM) or obesity are vulnerable to impaired gestational cardiovascular health (CVH) and cardiovascular disease (CVD) in the future. It is unclear if prenatal vitamin D supplementation improves gestational CVH, especially in women at high risk for developing CVD. Our goal was to find out if vitamin D supplementation could protect against gestational CVH, including the women with GDM or obesity. DESIGN: We randomly assigned women with a serum 25(OH)D concentration < 75 nmol/L to receive 1600 IU/d (intervention group) or 400 IU/d (control group) of vitamin D3 for two months at 24-28 weeks' gestation. The primary outcome was gestational CVH marks (lipids, inflammatory cytokines, endothelial function). RESULTS: There were 1537 participants divided into the intervention (N = 766) and control groups (N = 771). No baseline differences existed among study groups in CVH markers. At the two-month visit, the intervention group's HDL-C levels (2.01 ± 0.39 VS 1.96 ± 0.39 mmol/L) were significantly higher than those of the control group, while the hs-CRP levels were significantly lower (3.28 ± 2.02 VS 3.64 ± 2.42 mg/L). Subgroup analysis found that HDL-C, TC, hs-CRP, E-Selectin, and SBP were improved in the intervention group among women with GDM or overweight/obesity, and the improvement was not found in women without GDM or overweight/obesity. Vitamin D supplementation significantly decreased the mean triglyceride-glucose index at the two-month visit in women with GDM. CONCLUSIONS: Vitamin D supplementation at mid-gestation might optimize the gestational CVH status for pregnant women, particularly the women with GDM or obesity, which is advantageous for later-life primary prevention of CVD. CLINICAL TRIAL REGISTRATION: The Chinese Clinical Trial Registry (ChiCTR2100051914, 10/9/2021, Prospective registered, https://www.chictr.org.cn/showproj.aspx?proj=134700 ).

Minor Hydroxylated Triterpenoids Produced in Engineered Yeast by the Enzymes OSC and CYP716s from the Plant Enkianthus chinensis and Their Anti-Inflammatory and Hepatoprotective Activities.

Triterpenoids are a type of specialized metabolites that exhibit a wide range of biological activities. However, the availability of some minor triterpenoids in nature is limited, which has hindered our understanding of their pharmacological potential. To overcome this limitation, heterologous biosynthesis of triterpenoids in yeast has emerged as a promising and time-efficient production platform for obtaining these minor compounds. In this study, we analyzed the transcriptomic data of Enkianthus chinensis to identify one oxidosqualene cyclase (EcOSC) gene and four CYP716s. Through heterologous expression of these genes in yeast, nine natural pentacyclic triterpenoids, including three skeleton products (1-3) produced by one multifunctional OSC and six minor oxidation products (4-9) catalyzed by CYP716s, were obtained. Of note, we discovered that CYP716E60 could oxidize ursane-type and oleanane-type triterpenoids to produce 6ß-OH derivatives, marking the first confirmed C-6ß hydroxylation in an ursuane-type triterpenoid. Compound 9 showed moderate inhibitory activity against NO production and dose-dependently reduced IL-1ß and IL-6 production at the transcriptional and protein levels. Compounds 1, 2, 8, and 9 exhibited moderate hepatoprotective activity with the survival rates of HepG2 cells from 61% to 68% at 10 µM.

Highly sensitive detection of multiple antiviral drugs using graphitized hydroxylated multi-walled carbon nanotubes/ionic liquids-based electrochemical sensors.

Global outbreaks and the spread of viral diseases in the recent years have led to a rapid increase in the usage of antiviral drugs (ATVs), the residues and metabolites of which are discharged into the natural environment, posing a serious threat to human health. There is an urgent need to develop sensitive and rapid detection tools for multiple ATVs. In this study, we developed a highly sensitive electrochemical sensor comprising a glassy carbon electrode (GCE) modified with graphitized hydroxylated multi-walled carbon nanotubes (G-MWCNT-OH) and 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF6, IL) for the detection of six ATVs including famciclovir (FCV), remdesivir (REM), favipiravir (FAV), hydroxychloroquine sulfate (HCQ), cepharanthine (CEP) and molnupiravir (MOL). The morphology and structure of the G-MWCNT-OH/IL nanocomposites were characterized comprehensively, and the electroactive surface area and electron conductivity of G-MWCNT-OH/IL/GCE were determined using cyclic voltammetry and electrochemical impedance spectroscopy. The thermodynamic stability and non-covalent interactions between the G-MWCNT-OH and IL were evaluated through quantum chemical simulation calculations, and the mechanism of ATV detection using the G-MWCNT-OH/IL/GCE was thoroughly examined. The detection conditions were optimized to improve the sensitivity and stability of electrochemical sensors. Under the optimal experimental conditions, the G-MWCNT-OH/IL/GCE exhibited excellent electrocatalytic performance and detected the ATVs over a wide concentration range (0.01-120 µM). The limit of detections (LODs) were 42.3 nM, 55.4 nM, 21.9 nM, 15.6 nM, 10.6 nM, and 3.2 nM for FCV, REM, FAV, HCQ, CEP, and MOL, respectively. G-MWCNT-OH/IL/GCE was also highly stable and selective to the ATVs in the presence of multiple interfering analytes. This sensor exhibited great potential for enabling the quantitative detection of multiple ATVs in actual water environment.

CCDC146 is required for sperm flagellum biogenesis and male fertility in mice.

Multiple morphological abnormalities of the flagella (MMAF) is a severe disease of male infertility, while the pathogenetic mechanisms of MMAF are still incompletely understood. Previously, we found that the deficiency of Ccdc38 might be associated with MMAF. To understand the underlying mechanism of this disease, we identified the potential partner of this protein and found that the coiled-coil domain containing 146 (CCDC146) can interact with CCDC38. It is predominantly expressed in the testes, and the knockout of this gene resulted in complete infertility in male mice but not in females. The knockout of Ccdc146 impaired spermiogenesis, mainly due to flagellum and manchette organization defects, finally led to MMAF-like phenotype. Furthermore, we demonstrated that CCDC146 could interact with both CCDC38 and CCDC42. It also interacts with intraflagellar transport (IFT) complexes IFT88 and IFT20. The knockout of this gene led to the decrease of ODF2, IFT88, and IFT20 protein levels, but did not affect CCDC38, CCDC42, or ODF1 expression. Additionally, we predicted and validated the detailed interactions between CCDC146 and CCDC38 or CCDC42, and built the interaction models at the atomic level. Our results suggest that the testis predominantly expressed gene Ccdc146 is essential for sperm flagellum biogenesis and male fertility, and its mutations might be associated with MMAF in some patients.

Robust Tensor-Based DOA and Polarization Estimation in Conformal Polarization Sensitive Array with Bad Data.

Partially impaired sensor arrays pose a significant challenge in accurately estimating signal parameters. The occurrence of bad data is highly probable, resulting in random loss of source information and substantial performance degradation in parameter estimation. In this paper, a tensor variational sparse Bayesian learning (TVSBL) method is proposed for the estimate of direction of arrival (DOA) and polarization parameters jointly based on a conformal polarization sensitive array (CPSA), taking into account scenarios with the partially impaired sensor array. First, a sparse tensor-based received data model is developed for CPSAs that incorporates bad data. Then, a column vector detection method is proposed to diagnose the positions of the impaired sensors. In scenarios involving partially impaired sensor arrays, a low-rank matrix completion method is employed to recover the random loss of signal information. Finally, variational sparse Bayesian learning (VSBL) and minimum eigenvector methods are utilized sequentially to obtain the DOA and polarization parameters estimation, successively. Furthermore, the Cramér-Rao bound is given for the proposed method. Simulation results validated the effectiveness of the proposed method.

Prenylated C6-C3 derivatives from the root of Illicium ternstroemioides with antiviral activity.

Six previously undescribed prenylated C6-C3 derivatives (1-6) were isolated from the root of Illicium ternstroemioides A. C. Smith. Their structures were elucidated based on extensive spectroscopic analyses (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of 1-3 were determined using electronic circular dichroism (ECD), and Mo2(OAc)4 induced circular dichroism (ICD). Compound 3 exhibited weak activity against Coxsackievirus B3 with an IC50 value of 33.3 µM, and compound 5 exhibited more potent activity against Coxsackievirus B3 with an IC50 value of 6.4 µM.

Bioactive prenylated c6-c3 derivatives from the roots of Illicium brevistylum.

Three new prenylated C6-C3 compounds (1-3), together with two known prenylated C6-C3 compounds (4-5) and one known C6-C3 derivative (6), were isolated from the roots of Illicium brevistylum A. C. Smith. The structures of 1-3 were elucidated by spectroscopic methods including 1D and 2D NMR, HRESIMS, CD experiments and ECD calculations. The structure of illibrefunone A (1) was confirmed by single-crystal X-ray diffraction analysis. All compounds were evaluated in terms of their anti-inflammatory potential on nitric oxide (NO) generation in lipopolysaccharide-stimulated murine RAW264.7 macrophages and murine BV2 microglial cells, antiviral activity against Coxsackievirus B3 (CVB3) and influenza virus A/Hanfang/359/95 (H3N2). Compounds 3 and 4 exhibited potent inhibitory effects on the production of NO in RAW 264.7 cells with IC50 values of 20.57 and 12.87 µM respectively, which were greater than those of dexamethasone (positive control). Compounds 1 and 4-6 exhibited weak activity against Coxsackievirus B3, with IC50 values ranging from 25.87 to 33.33 µM.

Cadinane sesquiterpenes from the stems and branches of Illicium ternstroemioides.

Three new cadinane sesquiterpenes (1-3) and three known sesquiterpenes were isolated from the stems and branches of Illicium ternstroemioides A. C. Smith. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and HRESIMS data. The structures of illiternins A-C (1-3) were confirmed by single crystal X-ray diffraction, allowing for the determination of their absolute configurations. Compounds 3 and 6 exhibited antiviral activity against Coxsackievirus B3 with IC50 values of 33.3 and 57.7 µM, respectively.

A Low-Noble-Metal Ru@CoMn2O4 Spinel Catalyst for the Efficient Oxidation of Propane.

Noble metals have become a research hotspot for the oxidation of light alkanes due to their low ignition temperature and easy activation of C-H; however, sintering and a high price limit their industrial applications. The preparation of effective and low-noble-metal catalysts still presents profound challenges. Herein, we describe how a Ru@CoMn2O4 spinel catalyst was synthesized via Ru in situ doping to promote the activity of propane oxidation. Ru@CoMn2O4 exhibited much higher catalytic activity than CoMn2O4, achieving 90% propane conversion at 217 °C. H2-TPR, O2-TPD, and XPS were used to evaluate the catalyst adsorption/lattice oxygen activity and the adsorption and catalytic oxidation capacity of propane. It could be concluded that Ru promoted synergistic interactions between cobalt and manganese, leading to electron transfer from the highly electronegative Ru to Co2+ and Mn3+. Compared with CoMn2O4, 0.1% Ru@CoMn2O4, with a higher quantity of lattice oxygen and oxygen mobility, possessed a stronger capability of reducibility, which was the main reason for the significant increase in the activity of Ru@CoMn2O4. In addition, intermediates of the reaction between adsorbed propane and lattice oxygen on the catalyst were monitored by in situ DRIFTS. This work highlights a new strategy for the design of a low-noble-metal catalyst for the efficient oxidation of propane.

Synthesis of Taxifolin-Loaded Polydopamine for Chemo-Photothermal-Synergistic Therapy of Ovarian Cancer.

Chemotherapy is a well-established method for treating cancer, but it has limited effectiveness due to its high dosage and harmful side effects. To address this issue, researchers have explored the use of photothermal agent nanoparticles as carriers for precise drug release in vivo. In this study, three different sizes of polydopamine nanoparticles (PDA-1, PDA-2, and PDA-3) were synthesized and evaluated. PDA-2 was selected for its optimal size, encapsulation rate, and drug loading rate. The release of the drug from PDA-2@TAX was tested at different pH and NIR laser irradiation levels. The results showed that PDA-2@TAX released more readily in an acidic environment and exhibited a high photothermal conversion efficiency when exposed to an 808 nm laser. In vitro experiments on ovarian cancer cells demonstrated that PDA-2@TAX effectively inhibited cell proliferation, highlighting its potential for synergistic chemotherapy-photothermal treatment.

Integrating network pharmacology and experimental validation to investigate the effects and mechanism of Renshen Shouwu decoction for ameliorating Alzheimer's disease.

CONTEXT: The mechanism of Renshen Shouwu Decoction (RSSW) in treating Alzheimer's disease (AD) remains unknown. OBJECTIVE: This study investigates the effects and mechanism of RSSW for ameliorating AD. MATERIALS AND METHODS: Ten SAMR1 mice and 40 SAMP8 mice were divided into five groups: control (SAMR1), model (SAMP8), positive drug (Donepezil, 1.3 mg/kg/d), and RSSW (Low-dose, 117 mg/kg/d; High-dose, 234 mg/kg/d). Starting from 6 months of age, the medications were administered intragastrically for a total of 60 days. Subsequently, memory improvement in rapidly aging mice was assessed using the novel object recognition test and Morris water maze test. Through the identification of absorbed blood components and analysis of network pharmacology, active ingredients and potential targets involved in the treatment of AD were identified. Finally, AD-related biological indicators were detected using western blotting and ELISA. RESULT: Our results demonstrated that RSSW effectively ameliorated memory impairments, inhibited tau hyperphosphorylation, and reduced ß-amyloid plaque deposition in SAMP8 mice. Thirty absorbed blood components in RSSW were identified, revealing identified 96 major targets that play a key role in alleviating AD. Notably, the obtained main targets were highly enriched in SIRT1-mediated signaling pathways. Subsequent experimental validation confirmed that RSSW activated the SIRT1/NF-κB, SIRT1/AMPK, and SIRT1/p53 signaling cascades. Nine potential active ingredients were predicted through molecular docking. DISCUSSION AND CONCLUSIONS: Our research findings suggest the mechanism of RSSW treatment for AD, which ameliorates memory impairments by reducing cortical tissue inflammation and apoptosis.

[Study on changes of Styrax varieties].

Styrax is a commonly used imported traditional Chinese medicinal material in China. It was introduced to China in the Han Dynasty and was first described as a traditional Chinese medicine in Miscellaneous Records of Famous Physicians(Ming Yi Bie Lu). In this paper, by combing ancient and modern Chinese and foreign herbal medicine books and modern literature, combined with the results of field investigations on the origin of Styrax, the changes of Styrax involving the name, quality evaluation, origin, place of origin, and harvesting and processing were systematically verified. The results show that since ancient times, the origin and place of origin of Styrax have been unclear. The medical scientists of all dynasties in China have evaluated the quality of Styrax from four aspects: texture, viscosity, odor concentration, and color. The varieties of Styrax changed twice. The first change may have occurred during the Sui and Tang Dynasties, and the base changed from Styrax officinalis to Liquidambar orientalis. The second change was in modern times, and the base changed from L. orientalis to L. styraciflua. At the same time, the place of origin changed for the first time, from Turkey, Syria, and other countries in southern Asia Minor to Honduras, Guatemala, and other countries in Central America and southern North America. This paper studied the historical evolution of Styrax in terms of quality evaluation, origin, place of origin, character, and harvesting and processing. At the same time, it summarized the application of Styrax in the western countries, which can provide a historical basis for the further development and utilization of Styrax.

Characterization and Engineering of Two Highly Paralogous Sesquiterpene Synthases Reveal a Regioselective Reprotonation Switch.

Sesquiterpene synthases (STPSs) catalyze carbocation-driven cyclization reactions that can generate structurally diverse hydrocarbons. The deprotonation-reprotonation process is widely used in STPSs to promote structural diversity, largely attributable to the distinct regio/stereoselective reprotonations. However, the molecular basis for reprotonation regioselectivity remains largely understudied. Herein, we analyzed two highly paralogous STPSs, Artabotrys hexapetalus (-)-cyperene synthase (AhCS) and ishwarane synthase (AhIS), which catalyze reactions that are distinct from the regioselective protonation of germacrene A (GA), resulting in distinct skeletons of 5/5/6 tricyclic (-)-cyperene and 6/6/5/3 tetracyclic ishwarane, respectively. Isotopic labeling experiments demonstrated that these protonations occur at C3 and C6 of GA in AhCS and AhIS, respectively. The cryo-electron microscopy-derived AhCS complex structure provided the structural basis for identifying different key active site residues that may govern their functional disparity. The structure-guided mutagenesis of these residues resulted in successful functional interconversion between AhCS and AhIS, thus targeting the three active site residues [L311-S419-C458]/[M311-V419-A458] that may act as a C3/C6 reprotonation switch for GA. These findings facilitate the rational design or directed evolution of STPSs with structurally diverse skeletons.

Plasma-Excited Nebulizer Gas-Assisted Electrospray Ionization: Enhancing the Sensitivity of Pesticide in Mass Spectrometry.

Liquid chromatography-mass spectrometry (LC-MS) is widely used in the detection of pesticide residues. However, the detection sensitivity of low-polarity pesticides by commonly used electrospray ionization may be severely suppressed, which greatly affects the limit of detection and repeatability. Herein, a plasma-excited nebulizer gas-assisted electrospray ionization (PENG-ESI) device has been developed. By introducing the discharge plasma formed by Tesla coil into the electrospray nebulizer gas channel, the sensitivity of low-polarity pesticides was significantly increased while maintaining sensitivity to polar pesticides. Under the optimized conditions, the limit of detection for S-bioallethrin was achieved at the level of 100 pg/g with good linearity (R2 > 0.99) and precision (RSD ≤ 4.61%). The matrix effect of a series of spiked matrix samples is less than 13.1%. Finally, different pyrethroid pesticide residues were successfully analyzed without separation, highlighting that the technology has potential application prospects in food quality control, environmental monitoring, and other fields.

Multi-Targeted and On-Demand Non-Coding RNA Regulation Nanoplatform against Metastasis and Recurrence of Triple-Negative Breast Cancer.

Dysregulation of microRNAs (miRs) is the hallmark of triple-negative breast cancer (TNBC), which is closely involved with its growth, metastasis, and recurrence. Dysregulated miRs are promising targets for TNBC therapy, however, targeted and accurate regulation of multiple disordered miRs in tumors is still a great challenge. Here, a multi-targeting and on-demand non-coding RNA regulation nanoplatform (MTOR) is reported to precisely regulate disordered miRs, leading to dramatical suppression of TNBC growth, metastasis, and recurrence. With the assistance of long blood circulation, ligands of urokinase-type plasminogen activator peptide and hyaluronan located in multi-functional shells enable MTOR to actively target TNBC cells and breast cancer stem cell-like cells (BrCSCs). After entering TNBC cells and BrCSCs, MTOR is subjected to lysosomal hyaluronidase-induced shell detachment, leading to an explosion of the TAT-enriched core, thereby enhancing nuclear targeting. Subsequently, MTOR could precisely and simultaneously downregulate microRNA-21 expression and upregulate microRNA-205 expression in TNBC. In subcutaneous xenograft, orthotopic xenograft, pulmonary metastasis, and recurrence TNBC mouse models, MTOR shows remarkably synergetic effects on the inhibition of tumor growth, metastasis, and recurrence due to its on-demand regulation of disordered miRs. This MTOR system opens a new avenue for on-demand regulation of disordered miRs against growth, metastasis, and recurrence of TNBC.