EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Shuoning Wu,Ting Wang,Zhijie Mao,Zhentong Yang,Zhuoqun Wang,Zhuyin Jia,Zhouqing Huang,Yonghua Wang
Purpose Doxorubicin (DOX), a widely used chemotherapeutic agent for malignancies, exhibits dose-dependent cardiotoxicity, which restricts its clinical utility. While artesunate (ART) demonstrates potentially cardioprotective effects against acute DOX-induced cardiac damage, its role in chronic cardiotoxicity and its underlying mechanisms remain unclear. This study aimed to elucidate the mechanism underlying artesunate-mediated protection against doxorubicin (DOX)-induced cardiotoxicity. Methods Mice were treated with 5 mg/kg DOX (intraperitoneal injection) once weekly for 4 weeks to induce myocardial damage and with 25 mg/kg ART (intragastric administration) for 28 days. Echocardiography and histological staining were used to evaluate cardiac function and structural changes. We also assessed mRNA and protein levels using real-time polymerase chain reaction and Western blotting, respectively, and evaluated HuR-Sirt1 mRNA interaction via RNA immunoprecipitation (RIP). Results ART treatment significantly ameliorated DOX-induced cardiac dysfunction, fibrosis, hypertrophy, and apoptosis both in vivo and in vitro . Furthermore, ART restored cardiac sirtuin-1 (Sirt1) expression, which was suppressed by DOX. Critically, cardiac-specific Sirt1 knockout exacerbated DOX-induced cardiac damage and abolished the protective effects of ART. Mechanistically, we observed that siRNA-mediated HuR knockdown reduced Sirt1 expression, whereas Sirt1 knockdown did not affect HuR expression, indicating that HuR positively regulates Sirt1 expression. ART promotes the nuclear-to-cytoplasmic translocation of HuR, thereby enhancing its binding to Sirt1 mRNA and stabilizing Sirt1 transcripts. Conclusion Collectively, these findings demonstrate that ART attenuates DOX cardiotoxicity by activating the HuR-Sirt1 axis through the stabilization of Sirt1 mRNA.
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DOI
PubMed
高影响因子
Journal of the American Chemical Society
·
2025
·
IF 15.6
Qiu Wang,Yi Lin,Zijin Luo,Jiahui Xiao,Keqing Xu,Xiaolu Yu,Yanan Meng,Mengyao Li,Hongyu Ren,Fan Liu,Xiaoqiong Tan,Han Wen,Tuo Wei,Qiang Cheng
Conventional mRNA-LNPs typically self-assemble in acidic solutions through electrostatic interactions, necessitating long-term dialysis prior to use, which complicates the applications. In this study, a series of peptide ionizable lipids (PILs) were synthesized using solid-phase supported synthesis (SPSS) technology, aiming to utilize the amide bonds in PILs as hydrogen bond donors to form hydrogen bond-assisted mRNA-LNPs in RNase-free water, achieve extrahepatic targeted mRNA delivery, and simplify the preparation process. Through multiple rounds of optimization, a hydrogen bond-assisted two-component (2C) LNP platform composed of PILs and cholesterol was established. Among the 25 well-formulated 2C-PIL LNPs tested in vivo, 20 of them showed significant mRNA expression in the spleen, with a12K1 (2 amide bonds) and a12Orn4 (5 amide bonds) demonstrating the best performance. In addition, the two lead 2C-LNPs exhibited distinct transfection behaviors in different cell types in the spleen, indicating that suitable delivery vehicles can be tailored to meet the particular needs of specific disease indications. Notably, we found that among all K1-series (fewer hydrogen bond donors) LNPs, the efficacy of 2C-LNPs assembled based on hydrogen bond interactions was significantly higher than that of conventional four-component (4C) LNPs prepared via electrostatic interactions, suggesting that the 2C-LNPs platform may be a promising strategy to convert “inactive” LNPs into “active” LNPs. All together, these results suggest that the hydrogen bond-assisted 2C-LNPs can serve as an alternative and effective platform for spleen-targeted mRNA delivery and LNP optimization.
研究领域:
纳米医学
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药物递送
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分子生物学
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基因治疗
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生物材料
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PubMed
高影响因子
Acta Biomaterialia
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2017
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IF 6.319
Man Li,You Li,Ke Peng,Ying Wang,Tao Gong,Zhirong Zhang,Qin He,Xun Sun
Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo , which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency. Statement of Significance As we face outbreaks of pandemic diseases such as Zika virus , intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses.
研究领域:
疫苗学
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药学
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免疫学
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聚合物化学
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DOI
PubMed
高影响因子
Pharmaceutics
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2026
·Vol. 18
·期 4
·509
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IF 6.9
Kangling Xu,Junyu Su,Hailin Ma,Yanxia Zhu
Background/Objectives:Bone-targeted drug delivery systems hold great promise for treating skeletal diseases, yet the optimal strategy for functionalizing lipid nanoparticles (LNPs) with bone-homing ligands remains insufficiently explored. Herein, we compared two alendronate sodium (Alen) modification approaches (pre-conjugation and post-conjugation) for constructing bone-targeted LNPs capable of delivering mRNA to skeletal tissues.Methods:LNPs were fabricated via microfluidic mixing, and the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-alendronate conjugate (DSPE-PEG-Alen) required for the pre-conjugation method was synthesized. The bone-targeting ability of LNPs prepared by the two Alen modification strategies was evaluated using anin vitrohydroxyapatite (HAP) binding assay. Furthermore, the physicochemical properties, bone-targeting performance, mRNA delivery efficiency, and biosafety of the LNPs prepared by the post-conjugation method were assessed through cellular uptake,in vivoimaging, and other methods.Results:Hydroxyapatite binding assays revealed that the post-conjugation strategy afforded significantly superior bone affinity compared to the pre-conjugation approach. In addition, ex vivo bone fragment binding experiments further confirmed that the bone-targeting LNPs prepared by the post-conjugation method exhibited stronger bone-binding capability compared to unmodified LNPs. The optimized Alen-LNPs demonstrated efficient cellular uptake and functional mRNA translation in bone marrow mesenchymal stem cells with negligible cytotoxicity.In vivostudies in mice confirmed the preferential accumulation of Alen-LNPs in bone tissues, with successful green fluorescent protein (GFP) mRNA translation detected in bone tissue sections. Histopathological analysis confirmed the biosafety of the formulation.Conclusions:This study establishes the post-conjugation strategy as the superior approach for Alen functionalization of LNPs, providing a robust and reproducible platform for bone-targeted mRNA therapeutics.
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PubMed
高影响因子
HEPATOLOGY
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2026
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IF 18
Zhai Dongqing,Ni Jiaping,Shao Xianyu,Zhao Weijun,Chen Yuenan,Fan Kailin,Li Jingtong,Shen Yumeng,Lin Ang,Hu Weiwei,Yang Yong
Plain Language Summary Background and Aims: Liver fibrosis poses a major health threat globally, with an acute shortage of effective treatments to stop or reverse its progression. Hepatocyte injury serves as the primary cause of liver fibrosis, and restoring the expression of damaged proteins via mRNA delivery represents a promising therapeutic strategy. Clinical studies and animal models have demonstrated that mitochondrial ornithine transcarbamylase ( OTC ) deficiency correlates with increased incidence to liver fibrosis. In this study, we examined the therapeutic potential of OTC mRNA delivery of liver fibrosis. Approach and Results: Analysis of OTC expression and distribution in liver fibrosis revealed significant downregulation in fibrotic tissues. Restoring OTC expression in hepatocytes through AAV8-TBG-OTC significantly inhibits the progression of liver fibrosis. OTC mRNA sequences were developed using a codon-optimization artificial intelligence (AI) tool and synthesized with N1-methylpseudouridine modification followed by encapsulation into lipid nanoparticle (LNP). Repeated in vivo delivery of OTC mRNA-LNP induced a robust inhibition of fibrogenesis in multiple mouse liver fibrosis models. Mechanistically, restoring OTC mRNA expression significantly recovers impaired mitochondrial and hepatocyte functions, while concurrently inhibiting paracrine ammonia-induced activation of HSCs and macrophages. OTC mRNA significantly suppresses collagen deposition, while the THR- β agonist Resmetirom potently inhibits lipid accumulation; the combination exhibits potent complementary efficacy against metabolic dysfunction-associated steatohepatitis (MASH) liver fibrosis. Conclusion: Collectively, our study provides the first direct preclinical evidence supporting OTC mRNA therapeutics for treating liver fibrosis and establishes proof-of-concept for mRNA therapy as a novel strategy to reverse liver fibrosis. Export Plain Language Summary Liver fibrosis is a serious global health issue with limited treatment options. This study explores using mRNA therapy to restore the expression of ornithine transcarbamylase (OTC), a protein linked to liver health, as a treatment for liver fibrosis. Researchers used AI to optimize OTC mRNA sequences, which were then delivered to mice using lipid nanoparticles. This approach significantly reduced liver fibrosis by improving mitochondrial and hepatocyte functions and inhibiting harmful cell activation. OTC mRNA significantly suppresses collagen deposition, while the THR-β agonist Resmetirom potently inhibits lipid accumulation; the combination exhibits potent complementary efficacy against metabolic dysfunction-associated steatohepatitis (MASH) liver fibrosis. This research offers promising preclinical evidence for mRNA therapy in treating liver fibrosis. Text is machine generated and may contain inaccuracies. FAQ
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PubMed
高影响因子
Frontiers in Endocrinology
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2022
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IF 6.055
Jiayu Lin,Yuting Xiang,Jiana Huang,Haitao Zeng,Yanyan Zeng,Jiawen Liu,Taibao Wu,Qiqi Liang,Xiaoyan Liang,Jingjie Li,Chuanchuan Zhou
In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase ( OGA ) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA , we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein-coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a , Gm7788 , Gm41780 , Trpc7 , Gm29036 , and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation.
研究领域:
生殖生物学
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分子生物学
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细胞生物学
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PubMed
高影响因子
Nanoscale
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2020
·Vol. 12
·期 47
·24100-24106
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IF 6.895
Xia Li,Fang Yang,Chunfang Gan,Ruo Yuan,Yun Xiang
The simultaneous imaging of the dynamic expression variations of regulatory RNAs in cells, which remains a major challenge, has important applications in precise disease diagnosis, treatment and prognosis. Here, we describe the establishment of a biodegradable ZnO nanoparticle (NP)-assisted asymmetric amplification approach for the simultaneous imaging of microRNA-21 (miRNA-21) and programmed cell death 4 (PDCD4) mRNA at distinct expression levels in live cells. The DNA signal probe complexes are immobilized on the ZnO NPs and readily delivered into the target cancer cells via the endocytosis pathway. The acidic microenvironment in cancer cells leads to the dissolution of the ZnO NPs to release Zn2+ ions and the intracellular miRNA-21 activates the Zn2+-dependent DNAzyme to cleave the substrate signal probes with the assistance of the Zn2+ cofactor to show green fluorescence for imaging miRNA-21. Meanwhile, the PDCD4 mRNA can displace the other quenched signal probes to generate red fluorescence. Importantly, the PDCD4 mRNA sequences can be recycled and reused by using the DNAzyme-cleaved sequences as the fuel strands through two strand displacement reactions to yield amplified red fluorescence for detecting low levels of PDCD4 mRNA. Moreover, our approach can be used to evaluate the varied expression levels of miRNA-21 and PDCD4 mRNA responsive to different drugs in cells, reflecting its usefulness for precise cancer diagnosis and prognosis upon anticancer drug treatment.
研究领域:
分子生物学
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癌症研究
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纳米医学
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DOI
PubMed
高影响因子
eLife
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2025
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IF 0
Hai-Qian Zhou,Zhen Zhu,Jia-Wei Zhang,Wei-Peng Lin,Hao-JY Jin,Yang-Yang Ding,Shuai Liu,Dong-Min Yin
Precise regulation of protein synthesis is critical for brain functions such as long-term memory, and its dysregulation is implicated in numerous memory disorders. While mRNA methylation such as N6-methyladenosine (m6A) that has been widely studied in memory, the role of mRNA acetylation remains largely unknown. N4-acetylcytidine (ac4C), the only known form of RNA acetylation in eukaryotes, promotes mRNA stability and translation. In this study, we identified the ac4C epitranscriptome in mouse hippocampal homogenates and synaptosomes through ac4C-RNA immunoprecipitation followed by next-generation sequencing (acRIP-seq). The Morris water maze (MWM) was employed to induce and evaluate memory acquisition and forgetting processes. We show that synaptic ac4C levels are dynamically regulated, increasing after memory formation and returning to baseline after natural forgetting. The dynamic changes of ac4C-mRNAs regulated by memory were validated by ac4C dot-blot, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and acRIP-qPCR analysis. We further demonstrate that NAT10, the ac4C writer, in mouse hippocampus is important for spatial memory via regulating memory-related mRNAs, proteins, and ultimately synaptic plasticity. Lastly, we generated a freely-accessible website () that included the dataset of ac4C epitranscriptome in mouse hippocampus. Altogether these results demonstrate that dynamic and localized mRNA acetylation is a critical for synaptic plasticity and memory.
研究领域:
神经科学
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分子生物学
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表观遗传学
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RNA生物学
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认知科学
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DOI
ACS Applied Materials & Interfaces
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2018
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IF 8.097
Xiaoting Liu,Lei Wang,Xiaowen Xu,Haiyan Zhao,Wei Jiang
Drug resistance arising from overexpressed efflux transporters increases the efflux of drugs and accordingly restricts the efficacy of chemotherapy. Advances in nanocarriers have provided potential strategies to cope with drug resistance. Herein, endogenous stimuli-responsive nucleus-targeted nanocarrier is developed for intracellular multidrug resistance protein 1 (MRP1) mRNA imaging and drug delivery. This nanocarrier (AuNP–mRS–DSs) is composed of three parts: (i) gold nanoparticle (AuNP), for loading DNA and quenching fluorescence; (ii) mRNA recognition sequence (mRS) modified on the surface of gold nanoparticle by gold–thiol bond, for the specific recognition of MRP1 mRNA; (iii) detachable subunit (DS), hybridized with Cy5-labeled DNA linker and nucleolin recognition motif and grafted onto mRS via the DNA linker for loading doxorubicin (Dox), binding to nucleolin, and reporting signal. First, nucleolin recognition motif of this nanocarrier targets nucleolin, which is overexpressed on cancer cells surface; subsequently, the whole nanocarrier enters the cell via nucleolin-mediated internalization. Subsequently, mRS will specifically recognize overexpressed MRP1 mRNA, leading to the release of trapped DS and followed by AuNP-quenched Cy5 fluorescence recovery. Finally, by translocation of nucleolin from cytoplasm to nucleus, the DS targets nucleus to delivery Dox. By intracellular fluorescence imaging, the differentiation of drug-resistant and nondrug-resistant cells could be achieved. Compared with free Dox (IC50 > 8.00 μM), Dox-loaded AuNP–mRS–DSs (IC50 = 2.20 μM) performed superior suppression efficacy toward drug-resistant cancer cells. Such a nanocarrier provides an effective strategy to synergistically sense and circumvent drug resistance, which may be exploited as a candidate for personalized medicine.
研究领域:
纳米技术
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癌症生物学
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药学
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分子生物学
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DOI
PubMed
高影响因子
Nature Communications
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2026
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IF 15.7
Tianyao Li,Jingxin Zhang,Jing Guo,Bohong Sun,Yuxuan Han,Hu Xu,Yi Weng,Qinghao Cao,Min Li,Guangyu Zhao,Lin Liu,Xingfa Gao,Lianpan Dai,Daming Wang,Yuhong Cao
Messenger RNA (mRNA) therapeutics rely on lipid nanoparticles (LNPs) for delivery, yet inefficient endosomal escape remains a major bottleneck, with only a small fraction of internalized cargo reaching the cytoplasm. Conventional LNPs encapsulate mRNA in amorphous lipid cores, where partial charge neutralization and lack of structural order limit protonation-driven membrane disruption. Here, we present an architectural strategy that engineers LNP internal structure using ionizable lipid–coated gold nanoparticles (IC-AuNPs) as rigid, pH-responsive cores. The Au cores template the formation of radially ordered core–shell architectures that stabilize particles at physiological pH while amplifying charge segregation and curvature stress under acidic endosomal conditions. As a result, Au-LNPs achieve a twofold increase in endosomal escape and ~100-fold greater cytoplasmic mRNA diffusion compared to conventional LNPs. Functionally, Au-LNPs enhance mRNA expression in vitro, increases in vivo protein production up to sevenfold, boost antibody responses to SARS-CoV-2 vaccines, and improve therapeutic efficacy in a triple-negative breast cancer model. Lipid Nanoparticles (LNPs) effectively deliver mRNA to cells but suffer have low levels of endosomal release. Here the authors report on core-shell LNPs with ionizable lipid–coated gold nanoparticle cores with enhanced pH-responsive membrane disruption, endosomal escape, and cytosolic mRNA delivery improving therapeutic efficiency.
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PubMed
高影响因子
ADVANCED MATERIALS
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2026
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IF 29.1
Yanan Meng,Yi Lin,Zijin Luo,Xiaoqiong Tan,Xiaolu Yu,Hongyu Ren,Qiang Cheng,Chuan Fang,Tuo Wei
The endosomal escape capability of current mRNA-loaded lipid nanoparticles (mRNA-LNPs) is generally low, which restricts their overall delivery efficiency. To address this limitation, we adopted a strategy inspired by the viral infection mechanism, utilizing fusion peptides to enhance the intracellular release of mRNA. Nine viral-derived and artificial fusion peptides were co-encapsulated within mRNA-LNPs respectively, termed FP-LNPs, and systematically assessed their efficacy in improving mRNA delivery. Notably, the HA2 fusion peptide from the influenza virus demonstrated a marked enhancement in mRNA delivery efficiency both in vitro and in vivo. Under acidic conditions of endosomes, HA2 collaborates with ionizable cationic lipids to facilitate endosomal membrane rupture, thereby promoting the release of mRNA into the cytoplasm and enhancing protein expression. Moreover, the incorporation of fusion peptides into various types of mRNA-LNP formulations significantly improved their in vivo delivery efficiency of mRNA, resulting in improved gene editing outcomes in the liver and lungs. Furthermore, in a Hereditary Tyrosinemia Type 1 (HT-1) mouse model, HA2-LNP significantly boosted FAH protein expression in the liver and more effectively prevented body weight loss and reduced liver fibrosis. Overall, this approach offers a promising strategy for enhancing endosomal escape and boosting the delivery efficiency of mRNA, underscoring its enhanced therapeutic potential.
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PubMed
高影响因子
Materials Today
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2026
·
IF 22
Haowei Zu,Qiyue Sun,Tianyu Song,Xingdi Cheng,Shuai Liu,Chen Yang,Yixing Wen,Jingjiao Li,Rui Xie,Gongchen Wang,Jiaqi Lin,Jing Sun,Xueguang Lu
Mycoplasma pneumoniae (MP) remains a leading cause of community-acquired pneumonia in children and older adults, yet no licensed vaccine exists and intramuscular approaches fail to intercept infection at its mucosal portal. Here, we engineered an mRNA vaccine encoding four conserved MP antigens, formulated in tamibarotene-loaded lipid nanoparticles optimized for both intramuscular (IM) and intranasal (IN) administration. In mice, IM vaccination elicited high serum IgG and splenic T cell responses but generated negligible mucosal immunity. By contrast, IN administration induced robust bronchoalveolar IgA and expanded lung-resident memory T cells, while systemic IgG levels remained lower than with IM. Functionally, IN immunization conferred superior protection against MP challenge compared to IM immunization, reducing pulmonary MP load and lung pathology while demonstrating broad–spectrum efficacy against both MP strains 1 and 2. These head-to-head comparisons position intranasal mRNA‐LNP vaccination as a transformative strategy for safe, broadly protective vaccine for MP.
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高影响因子
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