COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
·
IF 5.6
Xiaolong Li,Lanlan Ma,Jueshuo Guo,Yaya Wei,Shijie Ma,Yaping Mai,Guojing Gou,Wenbao Zuo,Jianhong Yang
Melanoma is a highly aggressive form of skin cancer. mRNA vaccines deliver genetic material encoding specific antigens into cells, thereby triggering the host immune system to produce the antigen. Gp-100, an antigenic protein expressed on the surface of melanoma cells, serves as a target mRNA to stimulate the cytotoxic T lymphocyte (CTL) response. However, the absence of natural killer (NK) cells can lead to significant tumor cell proliferation. Gardiquimod, a TLR7 agonist, enhances NK cell cytotoxicity, promoting tumor clearance. In advanced melanoma, the unfolded protein response (UPR) often becomes dysregulated. By inhibiting protein kinase R-like ER kinase (PERK), the UPR can be disrupted, inducing apoptosis in cancer cells and shifting the tumor microenvironment (TME) towards an increased M1/M2 macrophage ratio. This study developed a cationic liposome-based mRNA vaccine (GD-LPR) using DOTMA to co-deliver gp-100 mRNA and the TLR7 agonist Gardiquimod, combined with the PERK inhibitor GSK2656157 (GSK), for synergistic melanoma immunotherapy. GD-LPR achieved 95 % mRNA encapsulation efficiency and demonstrated enhanced dendritic cell maturation and NK cell activation both in vitro and in vivo. In subcutaneous melanoma models, GD-LPR+GSK reduced tumor volume and prolonged survival by modulating the tumor microenvironment (TME): increasing CD8 + T cells (Fig. 3 f), repolarizing M2 to M1 macrophages (Fig. 4 f), and suppressing IL-10 while elevating pro-inflammatory cytokines (IL-2, IFN-γ, TNF-α). Mechanistically, GSK inhibited PERK/ATF-4 signaling, synergizing with GD-LPR to suppress lung metastasis. The combination of the GD-LPR vaccine and GSK provides new potential strategies for treating melanoma, particularly in subcutaneous tumors and lung metastases.
研究领域:
肿瘤学
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免疫学
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分子生物学
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转化医学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF POLYMER SCIENCE
·
2024
·
IF 3.9
Runcheng Tan,Guangqi Huang,Cong Wei,Zepeng He,Tianyu Zhao,Yi Shi,Zhijia Liu,Yongming Chen
Lipid nanoparticles (LNPs) have been demonstrated to be potent and well-tolerated vehicles for delivering mRNA in vaccination and therapeutics. However, the presence of anti-poly(ethylene glycol) (PEG) antibodies in the body resulted in the problems of hypersensitivity reaction, accelerated blood clearance and high systemic reactogenicity after repeated dosing of PEG lipid-contained LNPs, thus limiting the utility for in vivo messenger RNA (mRNA) delivery. Here, we synthesized well-defined polysarcosine functionalized lipids (pSar-lipids) with various hydrophobic tail lengths and molecular weights by the accelerated ring-opening polymerization of sarcosine N -carboxyanhydride (NCA). The obtained pSar-lipids were utilized as PEG lipid alternatives to explore structure–activity relationships of pSar-lipid-based LNPs. The results demonstrated that pSar-lipid-based LNPs by intravenous administration represented higher mRNA delivery efficiency in the liver and spleen with the increased hydrophobic tail length of pSar-lipids. Importantly, more significant preference for mRNA delivery into the liver was identified by increasing the molecular weight of pSar segments. As a result, this work elucidated the effect of structural variations in pSar-lipids on LNP-mediated in vivo mRNA delivery, providing clues to optimize pSar-lipids as potential alternatives to PEG lipids for developing next-generation of LNP delivery systems. Graphical
研究领域:
生物技术
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医学
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分子生物学
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DOI
高影响因子
JOURNAL OF COMPARATIVE NEUROLOGY
·
2022
·Vol. 531
·期 2
·294-313
·
IF 3.028
Xulin Li,Gaoyang Zhao,Hongren Huang,Jialin Ye,Junfeng Xu,Yuan Zhou,Xiaojuan Zhu,Liping Wang,Feng Wang
Many brain functions that underlie behavior, cognition, and emotions vary with age, as does susceptibility to neuropsychological disorders. The expression of specific genes that are involved in these functions, such as the genes encoding for oxytocin, its receptors, and apolipoprotein D, varies with age across different brain regions. The cannabinoid 1 receptor (CB 1 R) is one of the most widely spread G-protein coupled receptors in the central nervous system and is increasingly recognized for its important contribution to various brain functions. Although changes in CB 1 R expression with age have been reported in the male mouse brain, they have not been well investigated in the female brain. Here, we used fluorescence in situ hybridization to target CB 1 R mRNA in the whole brains of female C57BL/6J mice aged 4, 6, 12, 52 (12 months) and 86 weeks (20 months), and quantified CB 1 R-positive cells in 36 brain regions across the whole brain. The results showed that CB 1 R-positive cells number changed with age. Specifically, CB 1 R expression increased with age in some subregions of the cortex, decreased with age in the lateral septal area, and reached its lowest level at 52 weeks in the thalamus, hypothalamus, and hindbrain subregions. Cluster analysis revealed that some brain regions shared similar temporal characteristics in CB 1 R-positive cell number across the lifespan. Our results provide evidence that investigation of the neural basis of age-related characteristics of female brain functions is not only warranted but required.
研究领域:
神经科学
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分子生物学
·
衰老
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产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2023
·Vol. 190
·期 11
·1-9
·
IF 5.7
Wang Jing,Shi Lu,Tang Qiaorong,Zhu Xinyu,Wu Mengmeng,Liu Wei,Li Baoxin,Jin Yan
Nucleic acid lateral flow assay (NALFA) with gold nanoparticles (AuNPs) as colorimetric probes have been extensively adopted for point-of-care testing (POCT). However, the sensitivity of NALFA still needs to be improved. Herein, DNA-gold nanoaggregate (DNA-AuNA) was assembled as a signal amplification probe of NALFA for sensitive detection of tumor marker TK1 mRNA. Four functional oligonucleotides with complementary pairs were assembled to form DNA-AuNA that coupled more AuNPs to improve sensitivity. Thus, the limit of detection (LOD) was 0.36 pM, which is lower than that of conventional AuNPs-based NALFA. Moreover, the bioassay showed good reproducibility, stability, and specificity for detecting TK1 mRNA. The detection of TK1 mRNA in human serum was also satisfactory. Therefore, DNA-AuNA-based NALFA provides a sensitive method for portable detection of TK1 mRNA. Graphical abstract
研究领域:
生物化学
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分子诊断
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2024
·
IF 5.7
Liu Hui,Du Yating,Zhan Desheng,Yu Wenjun,Li Yan,Wang Aiping,Yin Jianpeng,Cao Haiqiang,Fu Yuanlei
Colorectal cancer (CRC) is the fourth most common cancer in the world, with the second highest incidence rate after lung cancer. Oxaliplatin (OXA) is a broad-spectrum anti-tumor agent with significant therapeutic efficacy in colorectal cancer, and as a divalent platinum analog, it is not selective in its distribution in the body and has systemic toxicity with continued use. Interleukin-12 (IL12) is an immunostimulatory cytokine with cytokine monotherapy that has made advances in the fight against cancer, limiting the clinical use of cytokines due to severe toxicity. Here, we introduced a long alkyl chain and N-methyl-2,2-diaminodiethylamine to the ligand of OXA to obtain OXA-LIP, which effectively reduces its toxicity and improves the uptake of the drug by tumor cells. We successfully constructed IL12 mRNA and used LNPs to deliver IL12 mRNA, and in vivo pharmacodynamic studies demonstrated that OXA-LIP combined with IL12 mRNA had better tumor inhibition and higher biosafety. In addition, it was investigated by pharmacokinetic experiments that the OXA-LIP drug could accumulate in nude mice at the tumor site, which prolonged the half-life and enhanced the anti-tumor efficiency of OXA. It is hoped that these results will provide an important reference for the subsequent research and development of OXA-LIP with IL12 mRNA, as well as provide new therapeutic approaches for the treatment of colon cancer. Graphical Abstract
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Lijie Qiao,Na Fan,Yupei Zhang,Yuting Chen,Shugang Qin,Xiangrong Song
Messenger RNA (mRNA) vaccine efficacy requires delivery systems that maximize antigen expression while precisely modulating innate immune activation. However, many conventional adjuvants induce type I interferons that inadvertently suppress mRNA translation, compromising vaccine efficacy. To overcome this limitation, we engineered a multifunctional lipid nanoparticle (LNP) by partially substituting a fraction of the structural lipid cholesterol with SitoC7A - a conjugate of sitosterol and the STING (Stimulator of Interferon Genes) agonist (C7A) linked via a reducible disulfide bond. This single SitoC7A component serves dual roles: its disulfide bond markedly enhances LNP uptake by dendritic cells (DCs) and boosts mRNA translation, while its C7A moiety selectively triggers STING signaling within DCs, avoiding systemic interferon responses. This integrated design yielded robust DC maturation and superior antigen presentation. In murine models, SitoC7A-LNPs encapsulating SARS-CoV-2 mRNA elicited potent protective immunity, while tumor antigen-loaded LNPs significantly suppressed lymphoma progression. We introduce a principle for the novel LNP design wherein a single engineered lipid simultaneously provides structural support, enhances mRNA delivery and expression specifically in key immune cells, and delivers spatially controlled adjuvanticity creating a versatile and potent platform for next-generation mRNA vaccines.
研究领域:
免疫学
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肿瘤学
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纳米医学
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疫苗学
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分子药剂学
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转化医学
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先天免疫
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2019
·Vol. 19
·期 6
·4579-4588
·
IF 1.851
Shiqi Wang,Fuwei He,Zhenwei Li,Yewen Hu,Ning Huangfu,Xiaomin Chen
Oxidative stress serves important roles in cardiac injury during the process of ischemia/reperfusion (I/R). Y‑box protein 1 (YB1), a member of the highly conserved Y‑box protein family, is closely associated with inflammation and stress responses by regulating gene transcription, RNA splicing and mRNA translation. However, the roles of YB1 in oxidative stress‑induced myocardial‑I/R (M‑I/R) injury are unknown. The aim of the present study was to examine the effects of YB1 on H2O2‑induced cardiomyocyte injury and its underlying mechanism. The results demonstrated that YB1 expression was upregulated during H2O2‑induced myocardial injury. YB1 knockdown through transfection of small interfering RNA significantly aggravated cardiac cell apoptosis. Furthermore, YB1 knockdown significantly reversed the H2O2‑mediated increase in phosphorylated signal transducer and activator of transcription (STAT)3, but did not affect the phosphorylation of P38, extracellular signal‑regulated kinases 1/2, c‑Jun N‑terminal kinases, P65, Janus kinase 1 and 2 or STAT1. Moreover, protein co‑immunoprecipitation and RNA‑binding protein immunoprecipitation assays revealed that YB1 interacted with protein inhibitor of activated STAT 3 (PIAS3) mRNA but not its translated protein. YB1 overexpression may have promoted PIAS3 mRNA decay, decreasing PIAS3 protein levels, and therefore increased the levels of phosphorylated STAT3. Finally, YB1 knockdown, mediated by a lentivirus carrying YB1 targeted short hairpin RNA, significantly decreased left ventricle percentage fractional shortening and ejection fraction values, while increasing the infarct sizes in a rat model of M‑I/R injury. These results demonstrated for the first time (to the best of our knowledge) that YB1 may protect cardiac myocytes against H2O2 or M‑I/R‑induced injury by binding to PIAS3 mRNA and resulting in the phosphorylation of STAT3.
研究领域:
心脏病学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-12
·
IF 39.3
Gu Yangzhuo,Yang Jingyun,He Cai,Zhao Tingmei,Lu Ran,Liu Jian,Mo Xianming,Wen Fuqiang,Shi Huashan
mRNA vaccines have emerged rapidly in recent years as a prophylactic and therapeutic agent against various diseases including cancer and infectious diseases. Improvements of mRNA vaccines have been underway, among which boosting of efficacy is of great importance. Pam2Cys, a simple synthetic metabolizable lipoamino acid that signals through Toll-like receptor (TLR) 2/6 pathway, eliciting both humoral and cellular adaptive immune responses, is an interesting candidate adjuvant. To investigate the enhancement of the efficacies of mRNA vaccines by Pam2Cys, the adjuvant was incorporated into mRNA-lipid nanoparticles (LNPs) to achieve co-delivery with mRNA. Immunization with the resulting mRNA-LNPs (Pam2Cys) shaped up the immune milieu in the draining lymph nodes (dLNs) through the induction of IL-12 and IL-17, among other cytokines. Antigen presentation was carried out mainly by migratory and dLN-resident conventional type 2 DCs (cDC2s) and significantly more potent antitumor responses were triggered in both prophylactic and therapeutic tumor models in a CD4 + and CD8 + T cell-dependent fashion. Accompanying memory antitumor immunity was also established. Moreover, the vaccine also stimulated much more robust humoral and cellular immunity in a surrogate COVID-19 prophylactic model. Last but not the least, the new vaccines exhibited good preliminary safety profiles in murine models. These facts warrant future development of Pam2Cys-incorporated mRNA vaccines or relevant mRNA therapeutics for clinical application.
研究领域:
免疫学
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肿瘤学
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传染病学
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分子生物学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 2
·1-14
·
IF 9
Zhang Shouyi,Lv Chengcheng,Niu Yichen,Li Changqi,Li Xiuming,Shang Yu,Zhang Yunchao,Zhang Yue,Zhang Yong,Zeng Yu
Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m 6 A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.
研究领域:
肿瘤学
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分子生物学
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Immunology Research
·
2024
·
IF 8.1
Meng Meng,Zhong Zhaoyang,Song Liang,Zhang Zhaohui,Yin Xiaofeng,Xie Xiqiang,Tian Lei,Wu Wei,Yang Yao,Deng Yafei,Peng Hongyan,Wu Shuting,Ran Guanghe,Lin Yuqing,Lai Qiangqiang,Bi Qinghua,Yan Fulin,Ji Yan,Wang Yang,Li Xiaohui,Yi Ping,Yu Jianhua,Deng Youcai
Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1–SAM signal axis in regulating NK-cell activation and effector functions.
研究领域:
免疫学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2022
·
IF 6.113
Li Tinghan,Wen Yibo,Guo Hangtian,Yang Tingting,Yang Haitao,Ji Xiaoyun
The accessory protein Orf6 is uniquely expressed in sarbecoviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an ongoing pandemic. SARS-CoV-2 Orf6 antagonizes host interferon signaling by inhibition of mRNA nuclear export through its interactions with the ribonucleic acid export 1 (Rae1)–nucleoporin 98 (Nup98) complex. Here, we confirmed the direct tight binding of Orf6 to the Rae1-Nup98 complex, which competitively inhibits RNA binding. We determined the crystal structures of both SARS-CoV-2 and SARS-CoV-1 Orf6 C-termini in complex with the Rae1–Nup98 heterodimer. In each structure, SARS-CoV Orf6 occupies the same potential mRNA-binding groove of the Rae1–Nup98 complex, comparable to the previously reported structures of other viral proteins complexed with Rae1-Nup98, indicating that the Rae1–Nup98 complex is a common target for different viruses to impair the nuclear export pathway. Structural analysis and biochemical studies highlight the critical role of the highly conserved methionine (M58) of SARS-CoVs Orf6. Altogether our data unravel a mechanistic understanding of SARS-CoVs Orf6 targeting the mRNA-binding site of the Rae1–Nup98 complex to compete with the nuclear export of host mRNA, which further emphasizes that Orf6 is a critical virulence factor of SARS-CoVs.
研究领域:
病毒学
·
分子生物学
·
结构生物学
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细胞生物学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2024
·
IF 5.4
Yuting Hou,Zhe Wang,Zhen Chen,Lan Shuai,Yifei Pei,Binbin Sun,Yuxin Jiang,Hongsheng Wang
It is difficult to obtain specific tumor antigens, which is one of the main obstacles in the development of tumor vaccines. The vaccines containing multivalent antigens are thought to be more effective in antitumor therapy. In this study, a mRNA encoding three neoantigens of melanoma were prepared and encapsulated into the mannosylated chitosan-modified ethosomes (EthsMC) to obtain a multivalent mRNA vaccine (MmRV) for transcutaneous immunization (TCI). MmRV can effectively induce maturation of dendritic cells, with a better performance than mRNA of a single neoantigen. TCI patches (TCIPs) loading MmRV or siRNA against PDL1 (siPDL1) were prepared and applied to the skin of melanoma-bearing mice. The results showed that TCIPs significantly increase the levels of TNF-α, IFN-γ, and IL-12 in both plasma and tumor tissues, inhibit tumor growth, as well as promote infiltration of CD4+ and CD8+ T cells in the tumor tissues. Furthermore, the combination of MmRV and siPDL1 showed much better antitumor effects than either monotherapy, suggesting a synergistic effect between the vaccine and PDL1 blocker. In addition, the treatment with the TCIPs did not cause damage to the skin, blood, and vital organs of the mice, showing good biosafety. To the best of our knowledge, this work is the first to construct a noninvasive TCI system containing MmRV and siPDL1, providing a convenient and promising approach for tumor treatment.
研究领域:
肿瘤学
·
免疫学
·
药学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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