JOURNAL OF CONTROLLED RELEASE
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2026
·
IF 12.4
Yu Han,Guohua Ma,Kai Zhang,Runcai Xu,Ning Xin,Jingtong An,Ning Wang,Yantao Li
Lipid nanoparticles (LNPs) have emerged as a powerful nanoplatforms contributing to the success of mRNA vaccines. However, the rational design of lipid structures and the optimization of LNP composition, especially via metal-based adjuvants to boost extrahepatic delivery and immune responses, represent a promising yet technically challenging strategy. Herein, we developed a Zn(II)-adjuvanted imidazole-based LNP system that integrates rational lipid design with metal-coordinated self-assembly to achieve synergistic enhancement in delivery and immunogenicity. Initially, a library of 28 imidazole-based ionizable lipids was synthesized and screened, identifying A10–1 LNPs with a well-balanced lipid composition and high transfection efficiency. Furthermore, Zn 2+ coordination with the imidazole headgroup imparts Zn-A10–1 LNPs with enhanced structural stability and delivery performance, leading to improved cellular uptake, efficient endosomal escape, and preferential accumulation in the spleen. These attributes contributed to the robust activation of bone marrow-derived dendritic cells (BMDCs), induced memory T cell responses, and elevated proinflammatory cytokine secretion. In a melanoma model, vaccination with Zn-A10–1 LNPs markedly suppressed tumor progression and promoted the infiltration of OVA-specific CD8 + T cells. Overall, this study underscores the potential of Zn(II)-coordinated LNPs as effective nanoplatforms for extrahepatic mRNA vaccine delivery, offering a promising strategy for the mRNA-based vaccine design and immunotherapies.
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iScience
·
2026
·
IF 4.5
Hao Sun,Xiaojing Qi,Shihan Chen,Yanshuang Huang,Xixi Zheng,Yaosheng Li,Ni Li,Jing Shi,Donghang Xu,Xiaoxu Hao,Yanli Zhao,Xianzhen Yin,Yue Hu,Yinghua Ying,Qin Chen,Yang Xia,Zhen Gu,Xuejin Li,Jianqing Gao,Tianyuan Zhang
Stem cell therapy has demonstrated significant therapeutic potential. However, the relatively large cellular diameter increases the likelihood of entrapment within capillaries, impeding the migration of stem cells to disease foci. We herein propose an enucleation strategy to enhance cell deformability, significantly improving vascular transit efficiency. Computational modelling, combined with experimental investigations using a microfluidic platform, revealed that increased cellular deformability, rather than a reduction in diameter, plays a greater role in facilitating cell transit, thereby challenging traditional perspectives on the cell mechanics. Observations of pulmonary vasculature using optical tissue clearing and fluorescence micro-optical sectioning tomography confirmed the extensive distribution of enucleated cells and their reduced entrapment within fibrotic foci. Consequently, enucleated mesenchymal stem cells efficiently deliver mRNA to the fibrotic sites, significantly mitigating pulmonary fibrosis. Our findings provide new insights into the role of enucleation in facilitating cellular transit through constricted vasculature and the underlying mechanobiology of enhanced deformability.
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Cell Death & Disease
·
2026
·Vol. 17
·期 1
·326
·
IF 12.2
Xin Hu,Meiqi Feng,Chengjin Qi,Boran Li,Hongjuan He,Kai Li,Lu Chen,Boshu Ji,Haoran Yu,Yue Zhao,Tong Wu,Ruiheng Ma,Yuhao Dong,Yan Zhang,Qiong Wu
Investigating the epigenetic mechanisms underlying lung adenocarcinoma (LUAD) through the lens of N 4-acetylcytosine (ac4C) modification could innovate cancer treatment strategies and targets. We used biological information methods to analyze shared data, with a focus on studying N -acetyltransferase 10 (NAT10), which is the only known ac4C “writer” protein. Our analysis revealed a significant upregulation of NAT10 expression in LUAD, a finding that was corroborated by investigations in both LUAD cancer tissue samples and cell lines. Subsequently, we employed CRISPR/Cas9 technology to knock out the NAT10 gene and analyzed the resulting knockout cells using acRIP-seq and RNA-seq techniques. Our findings demonstrated different expressions of the genes C-X-C motif chemokine ligand 5 (CXCL5) and DEK proto-oncogene (DEK), and functional enrichment analysis indicated a strong association with the adhesion signaling pathway. Laboratory experiments revealed that NAT10 acts as an ac4C “writer,” promoting the acetylation of CXCL5 and DEK and thus preventing the degradation of their mRNAs. Moreover, NAT10 was found to significantly affect the number of metastases and tumor growth following the injection of cancer cells into the tail vein of mice. Our research data suggests that targeting NAT10 has the potential to serve as a diagnostic biomarker or prognostic target for developing anti-metastatic therapies aimed at disrupting the adhesion process.
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PLoS One
·
2026
·Vol. 21
·期 3
·e0343144
·
IF 2.8
Xilian Li,Haihua Cheng,Yunpeng Fan,Binpeng Xu,Yang Xu,Qiang Gao
Nitrite accumulation poses a significant threat to aquatic organisms in intensive aquaculture systems. Macrobrachium rosenbergii , a commercially vital freshwater prawn, exhibits adaptive responses to environmental stressors, yet the molecular mechanisms underlying nitrite tolerance remain poorly understood. This study employed integrated mRNA and miRNA transcriptomics to dissect the regulatory networks activated in M. rosenbergii hepatopancreas under acute nitrite stress (0, 40, and 87.25 mg/L nitrite-N over 48 h). High-throughput sequencing revealed 640 and 912 differentially expressed genes (DEGs) in low-concentration (LC) and high-concentration (HC) groups, respectively, compared to controls (CK). In the LC group, enrichment was predominantly observed in ribosome biogenesis (96 genes, p < 0.001). Conversely, the HC group was characterized by the significant modulation of the PPAR signaling (11 genes), glycerophospholipid metabolism, and the citrate cycle ( p < 0.005). Calcium signaling and MAPK pathways may be central to stress adaptation across both groups. miRNA profiling revealed 17 downregulated and 2 upregulated miRNAs within the HC group relative to the CK group, with miR-193-y, miR-263-x, and miR-145-x implicated in metabolic regulation. Notably, novel miRNAs (e.g., novel-m0087-3p) showed concentration-dependent expression. qPCR validated the consistency of sequencing data, confirming stress-responsive genes ( P53 , HORMA , SLC25a28 ) and miRNAs. This study is the first to integrate the mRNA-miRNA regulatory network in Macrobrachium rosenbergii to elucidate the response mechanism to nitrite stress, emphasizing the role of metabolic reprogramming and signal pathway regulation as key survival strategies. It provides a foundation and novel perspectives for the molecular evolution of nitrite adaptability in aquatic animals and breeding programs.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Jianan Chen,Tong Xing,Jialei Song,Hang Zhang,Shaotian Fu,Lizhi Jiang,Yiqi Xu,Lei He,Huatao Liu,Hailong Ma,Xin Wang,Tangjun Zhou,An Qin,Peixiang Ma,Jie Zhao
The inflammatory environment mediated by TNF-α in the intervertebral disc can reduce the transfection efficiency of LNPs. • Engineered fibroblasts overexpressing TNF-α antibodies exhibit resistance to the decline in proliferation ability and activity induced by the inflammatory microenvironment. • Engineered fibroblasts rescue the inflammatory phenotype and ameliorate ECM homeostasis of degenerated nucleus pulposus cells in IVDD models in vitro and in vivo. Lumbar intervertebral disc degeneration (IVDD) is a prevalent degenerative condition lacking effective early-stage treatments. While fibroblast cell therapy and mRNA therapeutics represent promising approaches, their efficacy is limited by the inflammatory microenvironment of degenerated discs, which affects the delivery efficiency and compromises cell viability and gene delivery. To overcome these challenges, we developed an LNP-mRNA-engineered fibroblast strategy, utilizing fibroblasts as a “Trojan horse” for targeted mRNA delivery. In IVDD progression, inflammatory factors, particularly TNF-α, accumulate and exacerbate degeneration. Engineered fibroblasts mitigates TNF-α-induced senescence and proliferation arrest in inflammatory conditions, counteracts nucleus pulposus inflammation, and restores extracellular matrix production. In a rat IVDD model, engineered fibroblasts significantly improved disc height and showed superior therapeutic effects compared to naive fibroblasts. These results highlight the dual therapeutic mechanism of our approach, i.e. combining cell therapy with mRNA delivery, and its clinical potential in the treatment of IVDD. Download: Download high-res image (105KB) Download: Download full-size image
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Scientific Reports
·
2026
·
IF 4.9
Wang Yingnan,Wang Chang,Zhai Lin,Zhu Xiaoye
Cervical cancer is significantly associated with persistent infection of human papillomavirus (HPV) type 18, making accurate detection of low-abundance HPV-18 mRNA crucial for diagnosis and treatment. Current nucleic acid detection methods are often limited by complex instrumentation, time-consuming procedures, or fluorophore modifications. To address this, we developed an enzyme-free colorimetric biosensor by integrating a multicomponent nucleic acid enzyme (MNAzyme) with catalytic hairpin assembly (CHA) for signal amplification. In this strategy, target recognition triggers the formation of an active MNAzyme that cleaves a substrate hairpin, initiating a CHA cascade which releases G-rich sequences. These sequences form G-quadruplexes with peroxidase-like activity, catalyzing the oxidation of colorless TMB into a soluble blue product, enabling both visual detection and spectrophotometric quantification at 650 nm. Under optimized conditions, the biosensor achieved a detection limit of 6.92 pM for HPV-18 mRNA, allowing naked-eye identification of target levels as low as 10 pM. The platform exhibited high specificity and could be adapted to detect other HPV mRNA subtypes by simply modifying the recognition sequence. This work presents a universal, simplified, and sensitive colorimetric strategy with great promise for future development of point-of-care testing and viral analysis platforms.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Haijun Wang,Bao Jing,Xinyu Dong,Muning Wang,Yan Xuan,Siyao Chang,Yuxin Qin,Bojian Zhang,Weizhong Zhou,Sheng Wang,Yufeng Lin,Zhiyang Han
Vascular smooth muscle cells (VSMCs) are essential for maintaining vascular tone and participate in all stages of atherosclerosis. The transition of VSMCs into macrophage-like cells is a major source of plaque foam cells. Nevertheless, the mechanisms regulating this phenotypic transition remain elusive. RNA Binding Motif Protein 47 (RBM47) expression was increased by more than twofold in aortas of ApoE − / − mice and was markedly elevated in RBM47 + α-SMA + double-positive cells within atherosclerotic plaques. RBM47 knockdown significantly reduced plaque burden and vascular inflammation, and suppressed VSMC-to-macrophage-like transition. In POV-PC-treated VSMCs, RBM47 knockdown inhibited VSMC proliferation, migration, inflammation, and macrophage-like transition. Mechanistically, RBM47 was found to directly bind to two specific sequences within the 3′UTR of GALNT4 mRNA and enhance its stability. Functional rescue experiments confirmed that GALNT4 mediated the effects of RBM47 on VSMC-to-macrophage-like transition. These findings suggest that RBM47 contributes to atherosclerosis by stabilizing GALNT4 mRNA and promoting VSMC-to-macrophage-like transition.
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JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Qing Liang,Yue Peng,Linyao Zhao,Zhenlin Yang,Xiaowei Chen,Jinfei Li,Zhiyuan Wu,Kun Chen,Bolun Zhou,Yang Liu,Bin Hu,Chunfeng Qu,Moyan Zhang,Shugeng Gao
Neoadjuvant immunotherapy has transformed perioperative approaches for resectable non-small cell (NSCLC) by stimulating anti-tumor immunity preoperatively; however, approximately 50 % of patients fail to show clinical responses. Single-cell RNA sequencing identifies SPP1 + macrophages as a significant obstacle in NSCLC immunotherapy, yet scarce researches have focused on selectively targeting this subset. Herein, we engineer mannose-modified selective organ-targeting lipid nanoparticles (SORT LNPs) that co-load SPP1-siRNA and interferon-γ (IFN-γ) mRNA (siSPP1-mIFNγ@mLNPs) for lung-restricted, mannose receptor-guided delivery to SPP1 + macrophages. Co-encapsulation of siSPP1 and mIFNγ mRNA within mLNPs yields a synergistic effect that surpasses individual encapsulation, as it reverses the M2-like properties of SPP1 + macrophages, diminishes their tumor-promoting functions, and reprograms them towards a tumoricidal phenotype. When combined with the immune checkpoint inhibitors (ICIs) in vivo , siSPP1-mIFNγ@mLNPs significantly boost anti-tumor immune responses in both orthotopic lung cancer and pulmonary metastases. Overall, siSPP1-mIFNγ@mLNPs present innovative perspectives for precise cell-type targeting strategies and position SPP1 + macrophage reprogramming as a clinically actionable strategy to convert ICI non-responders into long-term survivors.
研究领域:
肿瘤学
·
免疫治疗
·
纳米医学
·
分子生物学
·
药物递送
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EXPERIMENTAL EYE RESEARCH
·
2024
·
IF 3
Di Li,Xuanyi Che,Ningning Gao,Jing Li
Previous studies have shown that the development of age-related cataract (ARC) is involved in lens epithelium dysfunction, which is associated with abnormally expressed circular RNAs (circRNAs). The current work aims to probe the role of circSTRBP (hsa_circ_0088,427) in hydrogen peroxide (H 2 O 2 )-induced lens epitheliums. Lens epithelium tissues were harvested from ARC or normal subjects (n = 23). CircSTRBP, spermatid perinuclear RNA binding protein (STRBP), and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (NOX4) levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation, cycle progression, and apoptosis were assessed using 5-ethynyl-2′-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and flow cytometry assays. Caspase 3 activity, reactive oxygen species (ROS), malondialdehyde (MDA), and Glutathione peroxidases (GSH-PX) levels were detected using corresponding kits. NOX4 protein level was determined using Western blot. The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and circSTRBP or NOX4 was assessed through RNA immunoprecipitation (RIP). CircSTRBP and NOX4 abundances were increased in lens epithelium samples from ARC patients and H 2 O 2 -treated SRA01/04 cells. CircSTRBP knockdown might abolish H 2 O 2 -triggered SRA01/04 cell proliferation repression and apoptosis and oxidative stress promotion. In mechanism, circSTRBP is bound with IGF2BP1 and improves the stability and expression of NOX4 mRNA in SRA01/04 cells. CircSTRBP facilitated H 2 O 2 -induced SRA01/04 cell apoptosis and oxidative stress through by enhancing NOX4 mRNA stability via recruiting IGF2BP1, providing novel insights for ARC progression and treatment.
研究领域:
分子生物学
·
细胞生物学
·
眼科学
·
生物化学
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BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Nayun Kim,Junhye Kwon,Ui Sup Shin,Joohee Jung
Colorectal cancer (CRC) is associated with high incidence and mortality rates. Targeted therapies for CRC cause various adverse effects, necessitating the development of novel approaches to control CRC progression. In this milieu, we investigated the anti-CRC effects of fisetin, a natural plant flavonoid. Cytotoxicity was performed in CRC patient-derived organoids (30 T and 33 T). Fisetin-induced tumor growth was evaluated in a CRC patient-derived organoid xenograft (PDOX) model. RNA sequencing, immunohistochemistry, and western blotting were performed subsequently. Fisetin significantly decreased organoid viability in a dose-dependent manner. In the PDOX model, fisetin significantly delayed tumor growth, showing a decrease in Ki-67 expression and the induction of apoptosis. In tumor tissues, four genes were identified as differentially expressed between the control and fisetin-treated groups. Among these, A-kinase anchoring protein 12 ( AKAP12 ) level was significantly increased by fisetin treatment (fold change > 2, p < 0.05). Notably, fisetin significantly inhibited vascular endothelial growth factor (VEGF) and epithelial cell adhesion molecule (EpCAM) via upregulation of AKAP12. Our results demonstrate the upregulation of AKAP12 mRNA and inhibition of angiogenesis by fisetin as a therapeutic strategy against CRC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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JOURNAL OF CHROMATOGRAPHY A
·
2024
·
IF 3.8
Liang-Zhi Qiao,Yuan-Zhi Tan,Shan-Jing Yao,Dong-Qiang Lin
In-depth knowledge of the pore structure of chromatographic resins is instrumental for better mechanistic understanding of adsorption performance, which can be translated into strategies to guide the design of new resins. Aiming to reveal the underlying reasons of low mRNA adsorption capacities of commercial oligo-dT resins, three-dimensional (3D) pore structure reconstruction was applied to relate key pore properties to the adsorption performance. The static 3D pore analysis revealed that the amount and connectivity of the accessible pores for 100 nm-sized mRNA reduced by over 90% and 46% compared with initial pore structure of resins, respectively, which led to discontinuous transport paths for mRNA. The dynamic simulations revealed that the strong hindrance of the firstly bound mRNA to the following mRNA molecules led to less than 10% of mRNA being able to penetrate into the resins with a depth of only 1–2 μm. Based on the digital material model, a virtual nanofiber-based macroporous resin was designed to explore its potential. Simulation results demonstrated that due to large pores and high connectivity, the new resin could allow over 91% of mRNA diffusion into the resin interior, showing great potential to improve the adsorption capacity of mRNA. This work provided a new method to evaluate the limitations of commercial oligo-dT resins and obtained some valuable guidance for the structure design of next-generation resins.
研究领域:
生物工程
·
生物技术
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BIOLOGY OF REPRODUCTION
·
2024
·
IF 3.1
Shi Heng,Zhao Xin-Hai,Peng Qin,Zhou Xian-Ling,Liu Si-Si,Sun Chuan-Chuan,Cao Qiu-Yu,Zhu Shi-Ping,Sun Sheng-Yun
Di(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer known for its toxic effects on the male reproductive system. Green tea polyphenols (GTPs), recognized for their antioxidant and anti-inflammatory properties, have demonstrated protective effects on various organs, but the mechanisms by which GTPs mitigate DEHP-induced testicular damage remain unclear. Healthy male C57BL/6J mice were divided into five groups: control, DEHP, DEHP + GTP treatment, GTP, and oil groups. Testicular histopathological changes were assessed using hematoxylin–eosin (H&E), periodic acid-Schiff (PAS), and Masson staining. Ultrastructural alterations were examined through transmission electron microscopy. High-throughput sequencing was performed to analyze the expression of mRNA, miRNA, and lncRNA and construct an lncRNA–miRNA–mRNA regulatory network for identifying key regulatory axes. Mice in the DEHP group exhibited significant testicular damage, including reduced sperm count, mitochondrial deformation, and endoplasmic reticulum dilation. GTP treatment notably improved testicular structural integrity, restored sperm count, and alleviated mitochondrial and endoplasmic reticulum damage. Additionally, DEHP significantly increased activated CD8+ T cells, which were reduced with GTP treatment. High-throughput sequencing revealed that GTP treatment exerted protective effects through the regulation of six key lncRNA–miRNA–mRNA axes. GTPs significantly protect against DEHP-induced testicular damage, and the lncRNA–miRNA–mRNA regulatory axes play a potential role in this process.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
·
药理学
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