Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Xiaoxuan Hong,Xianfu Li,Xiaolu Han,Jinghu Lou,Yue Li,Jintao Lin,Yi Cheng,Haonan Xing,Hui Zhang,Xiwei Wang,Shuang Zhang,Nan Liu,Zengming Wang,Chunying Cui,Aiping Zheng
During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro . We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Turkish Journal of Gastroenterology
·
2025
·Vol. 36
·期 7
·431
·
IF 1.6
Ying Jiang,Xinjie Wang,Zhenyang Wang,Shengliang Zhang,Jianhua Wang,Xianglong Wang,Yang Zhang
Background/Aims: Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy that carries a dismal prognosis. Tanshinone IIA (Tan-IIA) is involved in the regulation of N6-methyladenosine (m6A) modification and plays an anti-tumor role in HCC, but whether Tan-IIA regulates HCC by mediating m6A modification is unclear. Methods and Materials: Cell apoptosis, invasion, proliferation, viability, and stemness were estimated with flow cytometry, transwell, 5-ethynyl-2’-deoxyuridine, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, and sphere-forming assays. Methyltransferase-like 14 (METTL14) and 3 (METTL3) mRNA and protein levels were detected with reverse transcription-quantitative polymerase chain reaction and western blotting. Total m6A levels were measured using an m6A RNA methylation quantification kit. A possible regulation of tribbles pseudokinase-3 (TRIB3) expression by METTL3 in an m6A-modified manner was predicted through RM2Target and SRAMP and verified by m6A methylated RNA immunoprecipitation (MeRIP) and RIP. Mouse xenograft models assessed the action of Tan-IIA in HCC tumorigenesis. Results: Tanshinone IIA restrained HCC cell viability, proliferation, invasion, and stemness, and induced HCC cell apoptosis invitro, as well as repressed tumor growth in xenograft models. METTL3 and TRIB3 were upregulated in HCC samples and downregulated in Tan-IIA-treated HCC cells and xenograft tumors. METTL3 facilitated HCC cell viability, proliferation, invasion, and stemness by enhancing TRIB3 mRNA stability through m6A modification. Tan-IIA played its role by downregulating TRIB3, and Tan-IIA mediated TRIB3 expression by METTL3. Conclusion: Tanshinone IIA restrained HCC progression by regulating METTL3-mediated m6A modification of TRIB3 mRNA, offering evidence to support the clinical translation of Tan-IIA.
研究领域:
肿瘤学
·
分子生物学
·
表观遗传学
·
药理学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Yu-Juan Zhan,Chun-Miao Deng,Lin Tang,Shu-Jun Li,Tao-Yang Xu,Xian Wei,Xin-Yi Zhang,Can-Can Zheng,Li Deng,Cui Shao,Zhong-Min Ouyang,Alfred King-Yin Lam,Rong Zhang,Jun Liu,Xing-Yuan Shi,Zhen-Yu Pan,Wei Dai,Ming-Liang He,Simon Law,Xu Li,Xiao-Bing Chen,Cheng Zhou,Bin Li,Wen-Wen Xu
N-acetyltransferase 10 (NAT10)-catalyzed N4-acetylcytidine (ac4C) modification has been reported to drive tumor metastasis. Lysosomal dysregulation plays an important role in human diseases, but its function in esophageal cancer metastasis is unclear. It remains unknown whether NAT10 regulates lysosomal function, and the underlying mechanism and treatment strategy warrants investigation. Here, a novel role of NAT10 in inducing lysosomal acidification is revealed, and the clinical and biological significance of ATP6V0E1 in tumor metastasis is uncovered. Mechanistically, NAT10 promotes the translation efficiency of ATPase H + transporting V0 subunit e1 (ATP6V0E1) mRNA in an ac4C-dependent manner to facilitate ATP6V0E1 expression and vacuolar H + -ATPase (v-ATPase) activity, enhancing the lysosomal degradation of E-cadherin, ultimately accelerating tumor metastasis. Furthermore, G-749 is screened and identified as a novel NAT10 inhibitor capable of effectively impeding lysosomal acidification and tumor metastasis by disrupting the NAT10-Ubiquitin-specific Peptidase 39 (USP39) interaction. Overall, the results unveil a novel role of ac4C modifications in regulating lysosomal acidification and propose a potential strategy by targeting NAT10 to inhibit esophageal cancer metastasis.
研究领域:
癌症生物学
·
分子生物学
·
生物化学
·
细胞生物学
·
肿瘤生物学
·
RNA修饰
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Ji Wang,Yanhao Zhang,Shuo Dong,Wenhui Zha,Chao Liu,Yang Wang,Yuhao Jiang,Hanlei Xing,Xinsong Li
Lipid nanoparticles (LNPs)-based mRNA vaccines have shown great potential in the fight against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, it remains still a challenge to improve the delivery efficiency of LNPs and the long-term stability of their mediated mRNA vaccines. Herein, a novel ionizable lipid 2-hexyldecyl 6-(ethyl(3-((2-hexyldecyl)oxy)-2-hydroxypropyl)amino)hexanoate (HEAH) derived LNPs were developed for delivering the receptor binding domain (RBD) mRNAs. In vitro cell assays confirmed that the ionizable lipid HEAH with one ether bond and one ester bond derived LNPs possessed higher mRNA delivery efficiency compared with the approved ALC-0315 with two ester bonds used in the BNT162b2 vaccine. Notably, the HEAH-derived LNPs powder lyophilized did not significantly change for 30 days after storage at 37 °C indicating good thermostability. After two RBD mRNAs of Delta and Omicron variants were encapsulated into the HEAH-derived LNPs, a bivalent mRNA vaccine was obtained as a nanoparticle formulation. Importantly, the bivalent mRNA vaccine not only resisted Delta and Omicron and also generated protective antibodies against ancestral SARS-CoV-2. The HEAH-mediated bivalent vaccine induced stronger humoral and cellular immunity than those of the ALC-0315 group. Taken together, the ionizable lipid HEAH-derived LNPs show outstanding potential in improving the delivery efficiency of mRNA and the stability of mRNA vaccine.
研究领域:
药学
·
分子生物学
·
病毒学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Du Ailin,Chen Yingying,Qiao Siyu,Dong Jiaxing,Li Yulin,Cao Bokai,Zhao Rongyu,Zhang Ruiling
Introduction: Chronic alcoholism is one of the most common neurological diseases in modern society. However, the key mechanisms underlying learning and memory impairments caused by chronic alcohol exposure remain unclear. In this study, a microRNA-messenger RNA (miRNA-mRNA) network was constructed to explore the potential function of key genes in chronic alcohol exposure, their effects on the hippocampus, and their mechanisms which facilitate brain injury in mice.Methods: The Morris water maze test was used to assess the learning ability of mice in each group. Mitochondrial ATPase activity and H2S levels in the hippocampi of mice were determined. Differentially expressed miRNAs and mRNAs in the mouse hippocampus were identified using second-generation sequencing. Using the TargetScan, miRTarBase, and miRDB databases, we predicted miRNA target genes and constructed a miRNA-mRNA regulatory network. Furthermore, using the Gene Ontology and KEGG databases we performed functional enrichment and protein-protein interaction analyses. Real-time quantitative polymerase chain reaction (qPCR) and other methods were employed to verify the mRNA expression of related genes.Results: The Morris water maze test revealed that mice exposed to chronic alcohol exhibited a significantly reduced learning ability compared to the control group (p < 0.05). Compared with the control group, the activity of mitochondrial ATPase in the hippocampal tissue of alcohol-treated mice was significantly decreased (p < 0.01), suggesting brain injury. In the model group, H2S significantly increased in the mice hippocampi (p < 0.01), indicating that chronic alcohol exposure could activate cystathionineβ-synthase (CBS) and catalyze the mass formation of H2S, suggesting brain injury. A total of 208 differentially expressed miRNAs and 377 differentially expressed mRNAs were screened through bioinformatic analysis. Enrichment analysis indicated that the main pathways were involved in neurodegeneration and regulation of the Wnt signaling pathway. The PCR detected a significant downregulation in the expressions of FOS and EGR1 genes.Discussion: Consequently, chronic alcohol exposure may regulate the expression of FOS and EGR1 in the hippocampus through miR-222-3p, miR-132-3p, miR-212-3p, and miR-191-5p, reduce the activity of hippocampal mitochondrial ATPase, activate CBS, catalyze the large amount of H2S formation, and destroy the mitochondrial structure, resulting in decreased learning ability. Our findings revealed valuable genes and miRNAs for the study of chronic alcohol exposure.
研究领域:
神经生物学
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH
·
2025
·
IF 2.6
Shan Hui,Yi Long,Lemei Zhu,Wei Shi,Qing Zheng,Lihui Liang
Background Alzheimer’s disease (AD) is characterized by cognitive decline and neuronal loss, with cellular senescence emerging as a key driver. The insulin-like growth factor-1 receptor (IGF1R) pathway is implicated in aging and AD pathology. IGF2 mRNA binding protein 2 (IGF2BP2) can stabilize IGF1R mRNA, but its role in AD-associated neuronal senescence remains unclear. Methods We established AD mouse models and H 2 O 2 -induced senescent neuronal cell models to explore the impact of IGF2BP2 in neuronal senescence and cognitive deficits. RNA pull-down assays, methylated RNA immunoprecipitation (MeRIP)-qPCR, and behavioral tests were used to elucidate the molecular mechanisms and therapeutic potential of targeting IGF2BP2. Results IGF2BP2 was significantly up-regulated in the hippocampal neurons of AD mice. This upregulation correlated with increased β-amyloid (Aβ) deposition, neuronal damage, and cognitive impairments. In vitro , IGF2BP2 knockdown in H 2 O 2 -induced senescent neurons reduced IGF1R expression and alleviated neuronal senescence, as evidenced by decreased senescence-associated secretory phenotype factors and improved cell viability. Mechanistically, IGF2BP2 stabilized IGF1R mRNA through m6A modification, enhancing its expression. Knockdown of IGF2BP2 decreased IGF1R mRNA stability and expression, thereby mitigating neuronal senescence. In AD mice, IGF2BP2 knockdown improved cognitive function, reduced Aβ deposition, and delayed neuronal senescence. Conclusion IGF2BP2 contributes to neuronal senescence and cognitive deficits in AD by regulating IGF1R expression through m6A modification.
研究领域:
神经科学
·
分子生物学
·
表观遗传学
·
衰老研究
·
神经退行性疾病
✓ 已验证
DOI
PubMed
高影响因子
Journal of the American Chemical Society
·
2026
·
IF 16.6
Xiaofei Xin,Yifu Lyu,Huanyu Qin,Jinyu Dai,Di Wu,Yu Ding,Qiang Tian,Chao Qin,Na Li,Lifang Yin
The rational design of nonlamellar, multicompartment lipid nanoparticles (LNPs) offers a promising strategy for advancing nucleic acid delivery and immunotherapy. In this study, imidazole-based LNPs (A3-DM/DL-LNPs) with a mesoscopically disordered internal structure resembling the sponge phase were developed, enabling efficient codelivery of mRNA and STAT3-targeting siRNA (siSTAT3). Small-angle scattering analysis revealed a unique quasi-periodic arrangement in A3-DM/DL-LNPs, characterized by broader interdomain spacing and higher membrane heterogeneity compared to benchmark ALC-0315-LNPs, suggesting enhanced endocytosis efficiency and more favorable RNA encapsulation. The “M-shaped” polar headgroup, formed by a piperazine ring flanked by two imidazole moieties, promoted membrane interaction, cellular uptake, and transfection efficiency. In contrast, alternative LNPs with linear polar head structures (A3-SS/SM/SL-LNPs and A4-SS/SM/SL-LNPs) showed inferior delivery performance. Raman spectroscopy revealed that lipid spatial localization correlated with RNA expression in the spleen and lymph nodes, highlighting the importance of LNP structure in immune activation and targeting specific immune organs. Functionally, A3-DM/DL-LNPs restored dendritic cell (DC) antigen presentation, alleviated endoplasmic reticulum (ER) stress, and reversed T cell exhaustion in acute myeloid leukemia (AML), triggering strong immune responses and enhancing natural killer (NK) cell and T cell-mediated antileukemic activity, thereby improving therapeutic outcomes.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Man Gao,Xue Yang,Xiuxia Wang,Tong Liu
Preeclampsia (PE), a pregnancy-specific disorder characterized by placental dysfunction and severe maternal-fetal complications, involves ferroptosis—an iron-dependent cell death driven by oxidative stress and lipid peroxidation. This study investigated the role of zinc-finger protein 36 (ZFP36) in regulating ferroptosis in trophoblast cells and its underlying mechanisms. In vitro , hypoxia/reoxygenation was applied to human trophoblast HTR-8/SVneo cells to model ischemic injury. ZFP36 was found to inhibit oxidative stress and ferroptosis by suppressing nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Mechanistically, ZFP36 binds to the 3′ untranslated regions (3′UTRs) of NCOA4 mRNA, promoting its degradation and thereby attenuating ferritinophagy. In vivo , lentiviral overexpression of ZFP36 in a rat model of PE (induced by reduced uteroplacental perfusion pressure) alleviated clinical symptoms and reduced NCOA4-mediated ferroptosis. Collectively, these results demonstrate that ZFP36 regulates ferroptosis by modulating NCOA4-dependent ferritinophagy, offering a potential therapeutic strategy for PE through targeting ferroptosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2026
·Vol. 193
·期 1
·58
·
IF 5.3
Yin Zhaojiang,Zhang Jing,Li Binghui,Fan Hao,Wang Mei,Cui Hanfeng
A dual-mode sensor based on intramolecular catalytic hairpin assembly strategy (intra-CHA) is proposed for Survivin mRNA detection. Intra-CHA, a triplex complex of tetraferrocene-labeled H1/H2, shortens H1-H2 distance and increases their local concentrations, accelerating reaction by 2.8-fold vs. free-CHA. Ruthenium-based covalent organic frameworks (RuCOFs) with Ru(dcbpy) 3 2+ as luminophore has dual fluorescence-electrochemiluminescence (FL-ECL) properties. EDTA-incorporated RuCOFs@EDTA expands active sites, enhancing ECL efficiency 8-fold. Intra-CHA system is covalently conjugated to RuCOFs@EDTA through amide bond linkages. Target mRNA-triggered strand displacement reactions induce structural reconfiguration of the intra-CHA probes, resulting in controlled spatial segregation of tetraferrocene from the RuCOFs@EDTA interface. This results in the recovery of FL and ECL signals, enabling rapid and highly sensitive detection of Survivin mRNA. Experimental results show that the detection limits reach 0.04 fM (in the FL mode) and 0.009 fM (in the ECL mode) respectively, with excellent selectivity, stability, and reproducibility. The system has been successfully applied to detect Survivin mRNA in actual serum samples, providing a novel strategy for Survivin mRNA detection and paving the way for developing future diagnostic strategies for early cancer screening. Graphical
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2026
·
IF 6
Yijia Li,Jiaying Jin,Kemeng Chen,Siyu Yao,Long Yang,Yuxing Lin,Wenbing Dai,Hua Zhang,Bing He,Lei Miao,Qiang Zhang,Xueqing Wang
Pancreatic ductal adenocarcinoma (PDAC) is driven by KRAS mutations in over 90% of cases yet remains refractory to most therapies due to poor antigen delivery and a suppressive tumor microenvironment. To address these challenges, we developed an exosome‑augmented, epitope‑focused mRNA nanovaccine. First, we engineered a series-connected (SC) mRNA that condenses five immunodominant KRAS‑mutant epitopes (G12D, G12V, G12R and two other sequences) into a single open reading frame. This design minimizes non‑productive sequence and enhances antigen presentation compared to a conventional parallel-connected (PC) mixture of full‑length transcripts. Second, we cloaked β‑sitosterol LNPs with mature dendritic‑cell–derived exosomes (LNP@exo), endowing the particles with lymph‑node tropism and intrinsic adjuvanticity. The resulting mKRAS SC-LNP@exo triggered potent dendritic cell activation and Th1 cytokine release in vitro , rapidly accumulated in lymph nodes, and drove superior CD8⁺ T cell infiltration in a Pan02 tumor model. Remarkably, one‑third of mKRAS SC-LNP@exo treated mice achieved complete tumor regression without off‑target toxicity. These findings demonstrate that combining epitope‑condensed mRNA with exosome‑cloaked LNP delivery can convert “cold” KRAS‑mutant PDAC into an immunologically responsive tumor and provide a broadly applicable strategy for next‑generation mRNA cancer vaccines Download: Download high-res image (151KB) Download: Download full-size image
✓ 已验证
产品关联
DOI
高影响因子
PLoS Pathogens
·
2026
·Vol. 22
·期 5
·e1014007
·
IF 4.9
Xuejun Zhao,Xinyi Wang,Kejun Liu,Qian Fang,Cheng Wang,Guangbo Mei,Lihua Qu,Jiaxi Zhang,Jiayi Feng,Wenjuan Yang,Junnan Zhu,Hang Zhuo,Na Kuang,Xuebing Qiu,Zhigao Deng,Qiong Luo,Xiaoxia Jin,Lanxuan Jiang,Xiaoqing Li,Huifen Dong,Rui Zhou
Inhibiting the activation of hepatic stellate cells (HSCs) represents a key therapeutic strategy for alleviating liver fibrosis induced by schistosomiasis. Diverse cell populations secrete pro-inflammatory cytokines and chemokines, which induce HSC activation and thereby promote hepatic fibrosis progression. Tristetraprolin (TTP) exerts a pivotal role in the post-transcriptional regulation of pro-inflammatory cytokines by either accelerating mRNA degradation or suppressing translation, a regulatory mechanism closely associated with the pathogenesis of various hepatic disorders. However, the pathological roles of TTP in Schistosoma japonicum -induced liver fibrosis remain largely elusive. Here, we report that TTP is upregulated in the liver during S. japonicum -induced liver fibrosis, and its overexpression markedly ameliorates this fibrotic pathology in vivo . We further identify that TTP negatively regulates TGF-β1 mRNA stability by promoting N6-methyladenosine (m 6 A) RNA methylation, thereby inhibiting HSC activation. Mechanistically, TTP enhances transcription of the WT1-associated protein ( WTAP ) gene through its interaction with SMAD2/3. Furthermore, treatment with an m 6 A RNA methylation inhibitor confirms that TTP-mediated protection against S. japonicum -induced liver fibrosis, an effect associated with increased m⁶A RNA methylation in vivo . Thus, our findings uncover a novel and critical role of TTP in exerting its anti-fibrotic function via the WTAP/m 6 A epitranscriptomic machinery in the pathogenesis of S. japonicum -induced liver fibrosis. This finding provides a rationale for the therapeutic targeting of TTP-mediated m 6 A RNA methylation in S. japonicum -induced liver fibrosis.
Activation of hepatic stellate cells (HSCs) represents a pivotal event in the progression of schistosomiasis-induced liver fibrosis. Pro-inflammatory cytokines and chemokines secreted by injured hepatocytes and activated macrophage induce HSC activation. However, the underlying mechanisms governing the fine-tuned regulation of pro-inflammatory cytokines and chemokines gene expression during the progression of schistosomiasis-induced liver fibrosis remain largely elusive. As a key negative regulator of immune responses, the role of TTP in liver fibrosis remains controversial. Furthermore, while TTP has been reported to act as a transcriptional co-regulator and modulate gene expression at the transcriptional level, the majority of TTP-related studies have centered on its canonical role as a key mediator of mRNA degradation. Here, our study demonstrates that TTP attenuates S. japonicum -induced liver fibrosis via the regulation of TGF-β1 mRNA stability in an m 6 A-dependent manner. Specifically, WTAP-mediated m⁶A RNA methylation of TGF-β1 mRNA exerts a suppressive effect on HSC activation, thereby mitigating S. japonicum -induced liver fibrosis. Notably, our findings uncover a previously uncharacterized regulatory mechanism whereby TTP promotes WTAP transcription via direct interaction with SMAD2/3. These results demonstrate that TTP-driven transcriptional regulation of WTAP represents a novel mechanism underlying HSC activation, and further identify a potential strategy for intervening in S. japonicum -induced liver fibrosis.
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2026
·Vol. 98
·期 28
·20936-20944
·
IF 7.3
Liu Ziyu,Xie Lingling,Yin Shuhang,Zhu Xiaohua,Liu Meiling,Zhang Youyu
Cellular signaling networks are orchestrated by complex
interactions
between gene expression and ion flux, yet tools for simultaneously
visualizing these events in living cells remain limited. Herein, we
report two orthogonal gold-nanoparticle-based DNA nanosensors that
enable simultaneous imaging of sodium/hydrogen exchanger 1 (NHE1)
mRNA and Na + dynamics in hepatocellular carcinoma cells.
The sensing mechanism relies on proximity-dependent fluorescence quenching.
For mRNA detection, Cy3-labeled reporter strands hybridize to DNA-functionalized
gold nanoparticles (AuNPs), holding the fluorophore close to the quenching
surface. Target binding triggers strand displacement, releasing Cy3,
and restoring emission. For Na + detection, a Cy5-labeled
substrate strand hybridizes with a Na + -specific DNAzyme
anchored on AuNPs. Na + activates the DNAzyme, cleaving
the substrate at a defined site and liberating the Cy5 fluorophore.
This dual-sensor system enables the quantitative monitoring of both
analytes in living cells. Using this platform, we directly visualize
that NHE1 mRNA downregulation suppresses intracellular Na + accumulation, establishing a regulatory link between gene expression
and ion homeostasis. Notably, mRNA-targeted hybridization inhibits
cancer-cell migration in a dose-dependent manner, revealing a potential
therapeutic mechanism. This approach provides a molecular tool for
decoding ion-based signaling networks in cancer biology.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）