Cell Death & Disease
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2024
·Vol. 15
·期 12
·1-16
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IF 8.1
Hou Rui,Sun Xinrui,Cao Shiyao,Wang Yadong,Jiang Luo
The metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH + CD133 + FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3’UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC.
研究领域:
肿瘤学
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分子生物学
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代谢组学
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癌症生物学
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表观遗传学
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International Journal of Oral Science
·
2026
·Vol. 18
·期 1
·52
·
IF 17.6
Di Tiankai,Liu Yuhan,Li Zhili,Wang Lulu,Li Peiyi,Nian Meng,Zhou Dezhong,Niu Lina,Chen Yujiang
The age-related decline in the pro-angiogenic capacity of mature dental pulp stem cells (DPSCs) severely limits pulp regeneration. We identify impaired glycolytic metabolism, driven by reduced glucose transporter type 1 (GLUT1) and hexokinase 2 (HK2) expression, as the key mechanism, as its inhibition diminished endothelial tube formation. To reverse this, we developed an aminolyzed highly branched poly(β-amino ester) (HBPA) as a vector for GLUT1/HK2 mRNA co-delivery, achieving >90% transfection efficiency with excellent biocompatibility. In vitro, conditioned medium from reprogrammed mature DPSCs resulted in a 2.0-fold increase in capillary length and a 2.3-fold increase in branch points, restoring angiogenic potential to levels equivalent to those of immature DPSCs. This efficacy translated robustly in vivo, where a tooth root slice model showed reprogrammed cells generated tissue with a vessel density of 10.2 vessels per mm 2 , 2.5-fold higher than that of untreated controls. Crucially, this level of vascularization was statistically indistinguishable from that achieved by the benchmark immature DPSCs. Our study demonstrates that HBPA-mediated metabolic reprogramming effectively rejuvenates mature DPSCs by restoring the “Metabolic-ECM-Angiogenesis Axis”, offering a translatable strategy for predictable, vascularized pulp regeneration.
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SENSORS
·
2026
·Vol. 26
·期 3
·836
·
IF 3.5
Yixin Miao,Tao Zhou,Qinghong Ji,Min Hong
Cancer remains a leading global cause of death, with conventional treatments often limited by toxicity and recurrence. Recent advances in gene therapy and nanodrug delivery offer new avenues for precision oncology. Human telomerase reverse transcriptase (hTERT) and glutathione peroxidase 4 (GPX4) are overexpressed in many cancers and linked to apoptosis and ferroptosis, respectively. Here, we developed a manganese dioxide nanosheet (MnO2-NS) probe co-loaded with antisense oligonucleotides targeting hTERT and GPX4 mRNA to synergistically down-regulate both genes and induce dual cell death pathways. The probe, assembled via adsorption of fluorescently labeled antisense strands, showed controllable release in the presence of glutathione (GSH). Cellular uptake and antisense release were confirmed in multiple cancer cell lines. The MnO2-NS probe significantly suppressed cell proliferation, outperforming single-target or carrier-only controls. Molecular analyses confirmed reduced hTERT and GPX4 expression, along with GSH depletion, ROS accumulation, and elevated lipid peroxidation—collectively promoting enhanced cancer cell death. In summary, this MnO2-NS-based co-delivery system enables synergistic gene silencing and GSH depletion, enhancing antitumor efficacy and providing a promising strategy for multifunctional nanotherapy.
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JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Siyuan Tang,Lei Huang,Wu Wang,Gang Wu,Zhicong Zhao,Yuan Liu,Qiang Xia,Taihua Yang
Dilution mode (OD vs ID) reprograms LNP assembly and in vivo mRNA delivery. • ID yields smaller LNPs with lower EE and enhances hepatic mRNA expression. • OD produces LNP with larger particle size and elicits stronger antigen-specific IFN-γ secretion. Messenger RNA (mRNA)-loaded lipid nanoparticles (LNPs) are predominantly manufactured by microfluidic mixing, where extensive efforts have focused on optimizing upstream formulations and mixing parameters. In contrast, the influence of dilution methods on the final physicochemical properties and biological performance of mRNA/LNPs remains insufficiently understood. In this study, we systematically compared two representative downstream manufacturing methods, conventional off-line dilution (OD) and integrated in-line dilution (ID), using a design-of-experiments (DOE) strategy encompassing different flow rates (FR), flow-rate ratios (FRR), dilution ratios (DR). Across multiple formulations, ID consistently produced smaller nanoparticles with lower encapsulation efficiency and more negative surface charge than OD, whereas the dominant process parameter shifted from FRR under OD to DR under ID. These physicochemical differences were accompanied by distinct biological responses. ID-derived LNPs exhibited enhanced transfection in AML12 cells and increased hepatic mRNA expression following intramuscular administration, whereas OD-derived LNPs elicited stronger antigen-specific IFN-γ responses. Collectively, these findings suggest that dilution method continues to influence the maturation of mRNA/LNPs after microfluidic mixing and contributes to the establishment of their final physicochemical and biological characteristics. Download: Download high-res image (82KB) Download: Download full-size image
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MOLECULAR AND CELLULAR BIOCHEMISTRY
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2026
·
IF 4.7
Li Qianyu,Wang Huiyue,Chen Nan,Liu Xue,Li Yongle,Chen Lei,Gan Lu,Luan Yong
Postoperative cognitive dysfunction (POCD) is a common complication following surgery, particularly in elderly patients, and is closely linked to neuroinflammation driven by microglial activation. While dexmedetomidine (Dex) has shown neuroprotective potential in clinical settings, the molecular mechanisms underlying its beneficial effects—particularly in relation to RNA epigenetic regulation and metabolic reprogramming in microglia—remain poorly understood. Here, we uncover a novel mechanism by which Dex alleviates POCD through modulation of N6-methyladenosine (m 6 A)–dependent post-transcriptional regulation of pyruvate kinase M2 (PKM2). We demonstrate that Dex enhances the expression of the m 6 A reader protein YTHDF2, which recognizes m 6 A-modified PKM2 mRNA and promotes its degradation, thereby suppressing microglial glycolysis and neuroinflammation. In both in vitro and in vivo models, Dex treatment reversed surgery- or LPS-induced cognitive deficits, reduced pro-inflammatory cytokine production, and normalized metabolic shifts in microglia—effects that were dependent on YTHDF2-mediated PKM2 downregulation. Our findings uncovered a novel epigenetic mechanism by which Dex exerts neuroprotection and highlight YTHDF2-mediated PKM2 regulation as a potential therapeutic target for POCD.
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JOURNAL OF CONTROLLED RELEASE
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2025
·
IF 11.5
Jiangai Long,Sheng Ma,Renming Wan,Aolin Sun,Zhenyi Zhu,Ruoyi Wang,Zhaopei Guo,Wantong Song
Cationic polymers have garnered considerable attention as mRNA carriers due to their structural tunability and chemical diversity. Nevertheless, their broader application remains limited by poor stability under physiological conditions and cytotoxicity associated with excessive charge density. Here, we report thiourea-modified poly( l -lysine) (PLL-T) carriers constructed by combinatorial side-chain modification with ionizable and hydrophobic isothiocyanates. The resulting thiourea linkage introduced two hydrogen bonding donor sites, enabling stronger hydrogen bonding with mRNA. These hydrogen bonding could synergize with electrostatic and hydrophobic interactions, forming multiple cooperative interactions with mRNA. This design enhanced mRNA encapsulation, colloidal stability, and high transfection efficiency without increasing cytotoxicity. The optimized PLL-1A1B(T) variant achieved over 10,000-fold higher transfection efficiency than the parent polymer PLL, and outperformed the commercial gold-standard Lipofectamine MessengerMAX in both HEK293T and RAW264.7 cells. Compared with its amide-linked analogue PLL-1A1B(A), in which the amide linkage provided only a single hydrogen bonding donor site, PLL-1A1B(T) exhibited superior mRNA encapsulation (91 % vs. 42 %), higher storage stability, and over 50-fold increase in intramuscular transfection. Unlike PLL-1A1B(A), which induced high levels of inflammation, PLL-1A1B(T) exhibited minimal inflammation in vivo. Importantly, PLL-1A1B(T) enabled efficient delivery of mRNA cancer vaccines and elicited potent CD8 + T cell mediated antitumor immunity. A single administration of PLL-1A1B(T)@E6/E7 mRNA vaccine achieved 77 % tumor suppression rate (TSR) in the TC-1 tumor model. Moreover, in combination with anti PD-1, PLL-1A1B(T)@OVA mRNA vaccine achieved 90 % TSR in the B16-OVA tumor model. This study demonstrates hydrogen bonding-driven carriers engineering as a versatile strategy to tune nucleic acid-carrier interactions, offering a potent and safe platform for mRNA therapeutics.
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BIOSENSORS & BIOELECTRONICS
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2025
·
IF 10.5
Miao He,Jinhua Chen,MuRilege Chao,Wenting Cheng,Han Pan,Qiufeng Wang,Zhongyun Wang,Yang Xiang
mRNA vaccine had emerged as a novel and promising modality in cancer immunotherapy. As anti-tumor mRNA vaccines entered clinical trials, continuous monitoring of mRNA levels becomes particularly important. In this paper, a new method of collaborative detection of tumor mRNA vaccine by double Cas12a system based on split crRNA was created. Specifically, the target was extended based on the RCA ring template to generate RCA products and completed the first round of signal amplification; At this time, there were a lot of secondary structures in RCA products. Subsequently, the double Cas12a system with split crRNA bound to adjacent sites, reduced secondary structure of the DNA strand, stabilized the linearization state, and identified multiple sites at the same time, so as to achieve the second round of collaborative signal amplification. When there was no target in the system, the RCA reaction cannot be triggered. In this method, the entire detection process was completed by one-pot method. The detection limit was as low as 0.2pM, and it showed a good linear relationship in the range of 0–100 pM, which provided a new method for the screening and pharmacokinetics study of tumor mRNA vaccines.
研究领域:
癌症免疫治疗
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分子诊断
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CRISPR技术
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生物分析化学
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药代动力学
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核酸扩增
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ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2025
·
IF 4.2
Jingran Yang,Ruirui Ding,Ling Qi,Haoran Bi,Jianan Li
Cypermethrin (CMN) is a synthetic pyrethroid insecticide known for its neurotoxic effects, particularly in the hippocampus. To investigate the underlying molecular mechanisms, we conducted integrated microRNA (miRNA) and messenger RNA (mRNA) sequencing in HT22 hippocampal cells treated with 400 μM CMN. We identified 36 differentially expressed miRNAs and 170 target mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed significant involvement in cell adhesion, extracellular matrix organization, and signaling pathways such as phosphoinositide 3-kinase–protein kinase B signaling pathway (PI3K-Akt), mitogen-activated protein kinase (MAPK), and extracellular matrix (ECM)–receptor interaction. Using six topological algorithms, three hub genes (Col1a2, Fn1, and Pdgfrb) were finally identified. In addition, a miRNA–mRNA regulatory network was constructed, and expression patterns of key miRNAs and mRNAs were validated via reverse transcription polymerase chain reaction (RT-PCR). These findings highlight the critical role of the miRNA–mRNA regulatory network in CMN-induced neurotoxicity. The study provides valuable insights into potential therapeutic targets and preventive strategies for CMN-associated hippocampal damage.
研究领域:
毒理学
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神经生物学
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生物信息学
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分子生物学
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JOURNAL OF BIOLOGICAL CHEMISTRY
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2026
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IF 4.1
Dongsheng Xing,Hongwei Cao,Yan Yang,Shengyang Liu,Hanbing Yu,Zhenyu Liu,Kunrong Wang,Xin Wei,Aihui Yan
Tristetraprolin (TTP), which encodes an RNA-binding protein, was identified as a biomarker in three types of IgE-driven allergic tissues. Remarkably, in the nasal mucosa of the ragweed pollen-induced AR mouse model, TTP mRNA levels were increased approximately threefold. TTP overexpression in AR mice alleviated nasal inflammation and epithelial barrier damage, accompanied by reduced frequency of nasal spray and nasal friction, eosinophils/neutrophils/macrophages/goblet cells infiltration, and Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 secretion. The impact of TTP on the activation and differentiation of Th2 cells was assessed by utilizing naïve CD4 T cells isolated from mice. We found that TTP significantly suppressed Th2 activation and differentiation, as evidenced by the decreased levels of cytokines and the percentage of Th2. Transcriptomic profiling of CD4+ T cells (with/without TTP overexpression) was analyzed, and 14 down-regulated genes containing AU-rich elements (AREs) were obtained. The study concentrated on downregulated E3 ubiquitin ligase tripartite motif 18 (TRIM18) in TTP-overexpressed CD4+ T cells. Specifically, TTP protein bound to the ARE located at positions +3640 to +3644 (5’-UAUUU-3’) within the 3’UTR of mouse TRIM18, and this interaction reduces TRIM18 mRNA stability, a process that depends on the active-site residue Cys-139 within the second CCCH-type zinc finger motif of TTP. TRIM18 overexpression weakened the effects in CD4+ T cells induced by TTP overexpression. Collectively, TTP suppresses Th2 activation and differentiation in AR by modulating TRIM18 mRNA stability, highlighting their interaction as a critical pathway in allergic inflammation.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Changduo Wang,Yaming Guo,Xiaoyu Liang,Yujie Zhang,Kaijing Liu,Gen Li,Ni Zhu,Chunxiao Qi,Jiajia Shi,Chao Liu,Jianwu Dai,Jing Yang
A novel biodegradable polyester was designed to replace non-degradable cationic lipids, thereby eliminating long-term toxicity risks associated with mRNA delivery. • The ester-rich backbone facilitates endosomal/lysosomal escape, achieving superior VEGF mRNA transfection efficiency compared to conventional MC3- and DOTAP-based LNPs. • This polyester exhibits dual bioactivities: reactive oxygen species (ROS) scavenging and nitric oxide release, which synergistically mitigate oxidative stress and promote angiogenesis. Gene therapy has demonstrated promising efficacy in the treatment of peripheral arterial disease (PAD). However, conventional cationic lipids used in mRNA lipid nanoparticles (LNPs) lack degradable bonds, which may pose potential toxicity and long-term accumulation risks. Although many ionizable lipids have been designed with degradable ester linkages, the development of fully biodegradable cationic alternatives with favorable safety profiles remains of great interest. To address these limitations, we developed a biodegradable cationic alternative via ring-opening polymerization of ε-caprolactone initiated by triethanolamine, forming a three-armed polyester (3s-PCL) with tertiary ammonium groups. Subsequent conjugation with arginine or lysine yielded terminal-functionalized polyesters (3sPA /3sPL) as sustainable substitutes for conventional cationic lipids. In vitro and in vivo studies demonstrated that 3sPA-containing LNPs exhibit higher transfection efficiency than conventional LNPs (e.g., MC3- or DOTAP-based LNPs). Notably, arginine-modified 3sPA-LNPs displayed dual bioactivity: effective reactive oxygen species (ROS) scavenging and nitric oxide (NO) release. When loaded with VEGF mRNA, 3sPA-LNPs synergistically promoted angiogenesis in critical limb ischemia by elevating VEGF expression, reducing inflammation through ROS scavenging, and improving microcirculation via NO release. Collectively, these findings establish 3sPA-LNPs as a potent and safe mRNA delivery platform for critical limb ischemia, offering a promising treatment strategy for regenerative therapy. Download: Download high-res image (109KB) Download: Download full-size image
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Small
·
2015
·Vol. 12
·期 6
·756-769
·
IF 8.368
Yundong Zang,Yanchun Wei,Yujiao Shi,Qun Chen,Da Xing
A multifunctional nanoparticle based on gold nanorod (GNR), utilizing mRNA triggered chemo-drug release and near-infrared photoacoustic effect, is developed for a combined chemo-photoacoustic therapy. The constructed nanoparticle (GNR-DNA/FA:DOX) comprises three functional components: (i) GNR as the drug delivery platform and photoacoustic effect enhancer; (ii) toehold-possessed DNA dressed on the GNR to load doxorubicin (DOX) to implement a tumor cell specific chemotherapy; and (iii) folate acid (FA) modified on GNR to guide the nanoparticle to target tumor cells. The results show that, upon an effective and specific delivery of the nanoparticles to the tumor cells with overexpressed folate receptors, the cytotoxic DOX loaded on the GNR-DNA nanoplatform can be released through DNA displacement reaction in melanoma-associated antigen gene mRNA expressed cells. With 808 nm pulse laser irradiation, the photoacoustic effect of the GNR leads to a direct physical damage to the cells. The combined treatment of the two modalities can effectively destroy tumor cells and eradicate the tumors with two distinctively different and supplementing mechanisms. With the nanoparticle, photoacoustic imaging is successfully performed in situ to monitor the drug distribution and tumor morphology for therapeutical guidance. With further in-depth investigation, the proposed nanoparticle may provide an effective and safe alternative cancer treatment modality.
研究领域:
纳米医学
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癌症研究
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治疗诊断学
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分子生物学
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International Journal of Nanomedicine
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2023
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IF 8
Dawei Deng,Yang Li,Jianpeng Xue,Jie Wang,Guanhua Ai,Xin Li,Yueqing Gu
Messenger RNA (mRNA), a single-strand ribonucleic acid with functional gene information is usually abnormally expressed in cancer cells and has become a promising biomarker for the study of tumor progress. Hairpin DNA-coated gold nanoparticle (hDAuNP) beacon containing a bare gold nanoparticle (AuNP) as fluorescence quencher and thiol-terminated fluorescently labeled stem–loop–stem oligonucleotide sequences attached by Au–S bond is currently a new nanoscale biodiagnostic platform capable of mRNA detection, in which the design of the loop region sequence is crucial for hybridizing with the target mRNA. Hence, in this study, to improve the sensitivity and selectivity of hDAuNP beacon simultaneously, the loop region of hairpin DNA was screened by bioinformatics strategy. Here, signal transducer and activator of transcription 5b (STAT5b) mRNA was selected and used as a practical example. The results from the combined characterizations using optical techniques, flow cytometry assay, and cell microscopic imaging showed that after optimization, the as-prepared hDAuNP beacon had higher selectivity and sensitivity for the detection of STAT5b mRNA in living cells, as compared with our previous beacon. Thus, the bioinformatics method may be a promising new strategy for assisting in the designing of the hDAuNP beacon, extending its application in the detection of mRNA expression and the resultant mRNA-based biological processes and disease pathogenesis.
研究领域:
纳米技术
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分子生物学
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生物信息学
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癌症研究
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