ACS Applied Bio Materials
·
2025
·
IF 4.7
Honglei Zhang,Yizi Zhu,Jingxuan Ma,Yuqing Ma,Lijie Jin,Jing Li,Rui Yang,Gengshen Song
Lipid nanoparticle (LNP)-mRNA-based tumor immunotherapy needs to address challenges such as low efficacy of mRNA delivery, targeted protein expression, and compromised innate immunogenicity. Here, we screen a panel of 16 cyclic acetal-based ionizable lipid nanoparticles by in vitro and in vivo assays to develop a more effective and safer system specifically for tumor immunotherapy and mRNA delivery. Furthermore, by incorporating a cyclic acetal-based adjuvant lipid YK-TLR-001, two optimized cyclic acetal-based LNP formulations (YK-712 and YK-716) are demonstrated to enhance mRNA expression in the spleens and to induce exceptional maturation of antigen-presenting cells (APCs) and to promote antigen presentation. Moreover, animal studies treated with these formulations show activated cellular immunogenicity in healthy mice and inhibited tumor growth in the B16F10 melanoma model. Thus, the cyclic acetal-based LNPs with YK-TLR-001 present a promising direction in the design of mRNA vectors for the advancement of mRNA tumor immunotherapy.
研究领域:
生物医学工程
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免疫学
·
分子生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Mengfei Li,Xue Zheng,Xinyang Yu,Shaolong Qi,Shoujun Zhu,Guocan Yu,Songling Zhang
mRNA vaccines have been widely implemented and revolutionized the landscape of oncology and epidemiology. Potent vaccination demands precise control over injection depth to ensure optimal lymphatic drainage, driving the development of non-invasive imaging techniques to visualize the distribution and efficacy of mRNA vaccines. Herein, near-infrared-II (NIR-II) lipid nanoparticles (NIR-II-LNPs) are fabricated for mRNA delivery by integrating a cationic fluorophore amphiphile (IR780-C16) into traditional LNPs, enabling longitudinal, quantitative, and non-invasive trafficking of mRNA vaccines. The in vivo behaviors of mRNA vaccines are characterized with different vaccination protocols in mice and rabbits by NIR-II fluorescence imaging. Results proved that following a 25 µL injection of mRNA vaccines into the mouse thigh at a depth of 4 mm or a 500 µL injection volume into a rabbit at a depth of 7 mm via the intramuscular route, the vaccines rapidly and abundantly accumulated in the inguinal lymph nodes. Flow cytometry and tissue immunofluorescence analyses further validated that optimized vaccination parameters effectively activated antitumor immunity and greatly boosted the therapeutic efficacy in B16-OVA and HPV-associated mouse tumor models. NIR-II-LNPs offer a unique modality for non-invasively monitoring the fate of vaccines, reinforcing its role in preclinical and clinical mRNA therapeutics.
研究领域:
肿瘤学
·
免疫学
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生物医学工程
·
分子成像
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疫苗学
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产品关联
DOI
PubMed
高影响因子
Molecular Biomedicine
·
2025
·Vol. 6
·期 1
·1-14
·
IF 10.1
Ao Danyi,Peng Dandan,He Cai,Ye Chunjun,Hong Weiqi,Huang Xiya,Lu Yishan,Shi Jie,Zhang Yu,Liu Jian,Wei Xiawei,Wei Yuquan
Despite the declared end of the COVID-19 pandemic, SARS-CoV-2 continues to evolve, with emerging JN.1-derived subvariants (e.g., KP.2, KP.3) compromising the efficacy of current XBB.1.5-based vaccines. To address this, we developed an mRNA vaccine encoding the full-length spike protein of JN.1, incorporating GSAS and 2P mutations and encapsulated in lipid nanoparticles (LNPs). The JN.1-mRNA vaccine elicited robust humoral and cellular immune responses in mice, including high JN.1-specific IgG titers, cross-neutralizing antibodies, and increased T follicular helper (Tfh) cells, germinal center (GC) B cells, and T cell cytokines. Importantly, immunity persisted for up to six months and induced RBD-specific long-lived plasma cells. We also compared the immune responses induced by homologous and heterologous vaccination regimens, and our results demonstrated that the heterologous regimen—combining JN.1-mRNA with a recombinant protein vaccine (RBD JN.1 -HR)—induced stronger responses. These findings highlight the JN.1-mRNA vaccine constitutes an effective prophylactic approach against JN.1-related variants, as it induces potent neutralizing antibody responses across all tested lineages. This enhanced immunogenicity is expected to significantly reduce hospitalization rates and mitigate post-COVID complications associated with JN.1 and KP.3 infections. This study emphasizes the need for timely vaccine updates and the adaptability of mRNA vaccines in addressing emerging pathogens, providing a framework for combating future infectious diseases. Collectively, these results offer critical insights for vaccine design and public health strategies in response to emerging SARS-CoV-2 variants.
研究领域:
病毒学
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免疫学
·
疫苗学
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产品关联
DOI
PubMed
高影响因子
Molecular & Cellular Toxicology
·
2017
·Vol. 13
·期 1
·59-64
·
IF 1.25
Chen Jiahong,Zhang Hang,Aniagu Stanley,Jiang Yan,Chen Tao
Trichloroethylene (TCE) had been shown to induce aberrant DNA methylation changes in mouse liver, which could be critical in the development of hepatocellular carcinoma. To understand the effect of methionine, a methyl donor, on TCE-induced mouse liver cancer, we exposed B6C3F1 mice to TCE in the presence or absence of methionine. We found that supplementation with methionine attenuated the TCE-induced hypo- and hyper-methylation status of Cdkn1a and Ihh in mouse liver, respectively. The TCE-induced mRNA expression changes of Cdkn1a, Ihh and Jun were also alleviated by methionine. However, methionine supplementation accelerated the TCE-induced mRNA over-expression of Mki67, and enhanced the TCE-induced mRNA down-regulation of Dnmt3a and Tet2. In summary, our results showed that methionine could attenuate at least part of the TCE-induced DNA methylation changes, but the additional gene expression changes induced by supplementary of methionine does not support the assumption that methionine could prevent TCE-induced liver carcinogenesis.
研究领域:
毒理学
·
分子生物学
·
癌症研究
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DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yichen Li,Yi Cao,Hao Bai,Luwei Zhang,Baiqiu Chen,Chengfan Wu,Qi Shuai,Yunfeng Yan
The application of mRNA-based therapies has gained significant attention in recent years, with lipid nanoparticles (LNPs) emerging as key delivery vehicles. However, challenges remain in optimizing delivery efficiency and targeting tissues beyond the liver, particularly for immunotherapy. In this study, we constructed novel lipids with disulfide bonds in the linkers and utilized the redox responsiveness of these bonds in the reductive microenvironment of tumor or immune cells to enable robust splenic mRNA delivery and potent cancer immunotherapy. A library of 119 lipids was synthesized by conjugating hydrophilic amines, disulfide-containing linkers, and hydrophobic amines via sequential aza-Michael addition. In vitro screening identified lipids with longer, branched hydrophobic tails, particularly 2C10, as leading carriers for mRNA delivery. Compared to conventional LNPs without disulfide linkers, disulfide-containing LNPs showed smaller size, higher mRNA binding, and enhanced mRNA release in the presence of GSH, with predominantly spleen-targeted in vivo delivery. Encapsulation with OVA mRNA promoted CD4 + and CD8 + T cell differentiation, leading to significant tumor regression in a melanoma mouse model. These findings highlight the potential of redox-responsive LNPs for targeted mRNA delivery and cancer immunotherapies.
研究领域:
生物技术
·
药理学
·
免疫学
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产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Xinning Yu,Tengjing Xu,Huimin Shi,Jianqiao Hong,Xiaoqiang Jin,Le Cao,Jiajie Wang,Yunting Lin,Zongyou Pan,Siheng Wang,Jinghua Fang,Kaiwang Xu,Hongyun Song,Zhuxing Zhou,Sunan Zhu,Jun Yin,Yiying Qi,Xuesong Dai
Integration of repair tissue with host cartilage is challenging. The persistent and drastic hypocellular interface resulting from perifocal chondrocyte apoptosis, leads to failure of cartilage repair over time. Recombinant insulin-like growth factor-1 (IGF-1) has been shown to inhibit chondrocyte apoptosis in vitro. However, low bioactivity, limited penetration and short retention are its drawbacks. Herein, a cartilage targeting ionizable lipid nanoparticle (LNP) is developed. Messenger RNA (mRNA) encoding IGF-1 is chemically modified and encapsulated by LNP (mRNA-LNP). CAQK, a peptide previously used for targeted delivery to the central nervous system, is introduced to mRNA-LNP (mRNA-cLNP) to bind aggrecan enriched in cartilage. As a result, mRNA-cLNP exhibits improved penetration of cartilage and prolonged retention in the joint cavity. The mRNA-cLNP also showed robust reversal of chondrocyte apoptosis. In a full-thickness chondral defect plus microfracture model, mRNA-cLNP maintained interfacial cellularity and prevented matrix degradation in cartilage-cartilage interface. This study shows that mRNA-cLNP is a promising therapeutic agent for integrative cartilage repair.
研究领域:
骨科
·
生物医学工程
·
组织工程
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DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Haihong Yang,Zhan Gao,Yizi Zhou,Xueer Ge,Xiaorong Pan,Jiakun Li,Zhihui Zhang,Xuanli Jin,Guotao Liu,Zepeng He,Hong Liu,Zhijia Liu,Lixin Liu,Yongming Chen
Lipid nanoparticles (LNPs) have emerged as a groundbreaking platform for delivering messenger RNA (mRNA)-based vaccines and therapeutics. However, clinically approved LNPs administered intramuscularly often lead to unintended liver antigen expression, raising safety concerns related to excessive immune activation and potential tissue damage. Extensive research has focused on optimizing LNPs to adjust their tissue specificity and immunogenicity, while the role of helper lipids as structural components has received little attention. Here, we developed a new LNP system by replacing traditional phospholipids with innovative tertiary amine N -oxide zwitterionic lipids (AOLs) synthesized using the Ugi four-component reaction (Ugi-4CR) followed by tertiary amine oxidation. After two rounds of structural screening and optimization, three top-performing AOL-based LNPs demonstrated muscle-selective mRNA delivery with minimal off-target effects. Using ovalbumin (OVA)-encoded mRNA as a model antigen, the optimized LNP-mRNA vaccine effectively activated more migratory and resident cDC1 cells in muscle and lymph nodes (LNs), increasing tumor CD8 + T cell infiltration and thus inhibiting tumor growth in a murine melanoma model, compared to the benchmark SM-102 LNP. Furthermore, co-formulating CpG adjuvants with the LNP-mRNA vaccine amplified cDC1-mediated antitumor efficacy. In addition, AOL-based LNP-mRNA vaccines reduced the infiltration of CD3 + CD45 + T cells in the liver, decreasing the risk of liver inflammatory responses. As a result, we provide a safe and efficient LNP system for muscle-selective mRNA vaccine delivery, enhancing cDC1-mediated antitumor treatment and offering a promising strategy for tumor immunotherapy.
研究领域:
生物医学工程
·
免疫学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
·
2023
·
IF 9.7
Jiaoshun Chen,Haoxiang Zhang,Chaoyang Xiu,Chenggang Gao,Shihong Wu,Jianwei Bai,Qiang Shen,Tao Yin
In eukaryotes, N 6 -methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.
研究领域:
癌症生物学
·
分子生物学
·
表观遗传学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Kexin Zhang,Zhen Xu,Zexiu Xiao,Fei Cao,Jing Wang,Yuandong Xu,Winson M.J. Ma,Sihui Long,Gao-Feng Zha
Lipid nanoparticles (LNPs) have emerged as a clinically validated platform for cancer immunotherapy; however, challenges remain in optimizing RNA delivery and promoting synergistic immune activation. To address these issues, we developed a modified LNP system that incorporates α-galactosylceramide (α-GalCer), a CD1d-binding glycolipid known to activate invariant natural killer T (iNKT) cells. Through structural optimization, we created the α-GalCer-LNP (G-LNP), which offers three primary advantages over conventional four-component LNPs: (1) enhanced mRNA transfection efficiency due to improved endosomal/lysosomal escape, (2) increased capacity for in vivo DC transfection, leading to robust activation of tumor-specific CD8 + T cells via MHC-I and iNKT cells via the CD1d pathway, and (3) reprogramming of the tumor microenvironment, resulting in a 1.5-fold increase in iNKT cell infiltration and sustained elevation of IFN-γ (>24 h) in lymph nodes. In a TC-1 cervical carcinoma model, G-LNP induced complete tumor regression in 100 % of treated mice (compared to 42.85 % for standard LNP) and provided long-term protection against tumor rechallenge (lasting >100 days). Mechanistic studies showed that G-LNP preferentially targets CD11c + DC in the lymph nodes, facilitating coordinated antigen presentation and innate immune activation. This five-component engineering strategy establishes a versatile platform to enhance the functionality of LNPs for the development of next-generation cancer vaccines.
研究领域:
免疫学
·
肿瘤学
·
纳米医学
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产品关联
DOI
PubMed
高影响因子
Emerging Microbes & Infections
·
2024
·
IF 8.4
Anke Chen,Ning Fang,Zhifei Zhang,Yiqing Wen,Yajie Shen,Yanjie Zhang,Lu Zhang,Guoping Zhao,Jin Ding,Jixi Li
The global outbreak of Mpox, caused by the monkeypox virus (MPXV), has attracted international attention and become another major infectious disease event after COVID-19. The mRNA cap N7 methyltransferase (RNMT) of MPXV methylates the N7 position of the added guanosine to the 5'-cap structure of mRNAs and plays a vital role in evading host antiviral immunity. MPXV RNMT is composed of the large subunit E1 and the small subunit E12. How E1 and E12 of MPXV assembly remains unclear. Here, we report the crystal structures of E12, the MTase domain of E1 with E12 (E1CTD-E12) complex, and the E1CTD-E12-SAM ternary complex, revealing the detailed conformations of critical residues and the structural changes upon E12 binding to E1. Functional studies suggest that E1CTD N-terminal extension (Asp545-Arg562) and the small subunit E12 play an essential role in the binding process of SAM. Structural comparison of the AlphaFold2-predicted E1, E1CTD-E12 complex, and the homologous D1-D12 complex of vaccinia virus (VACV) indicates an allosteric activating effect of E1 in MPXV. Our findings provide the structural basis for the MTase activity stimulation of the E1-E12 complex and suggest a potential interface for screening the anti-poxvirus inhibitors.
研究领域:
病毒学
·
结构生物学
·
分子生物学
·
传染病学
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DOI
高影响因子
ANALYTICAL CHEMISTRY
·
2020
·
IF 6.785
Peng Miao,Yuguo Tang
Messenger RNA (mRNA) is a type of important gene regulation element and reliable biomarker for the early diagnosis of diseases. However, mRNA analysis in live cells cannot be easily realized since conventional techniques always require procedures like mRNA purification or cell fixation. Herein, we propose a powerful two-dimensional hybridization chain reaction (2D HCR) strategy for amplified sensing and imaging of intracellular mRNA. The basis is the design of ternary hairpin or dumbbell-structured DNA fuel strands. In the presence of mRNA, organized 2D DNA assembly reaction can be initiated, which leads to structural changes of a large number of fuel strands and produces an in situ 2D DNA network. An enhanced fluorescence signal is thus generated, allowing direct and quantitative analysis of mRNA with high signal-to-noise ratio. Moreover, MnO2 nanosheet/glutathione-aided transportation and release association are successfully applied to adapt the 2D HCR nanosystem in live cells. Therefore, this work provides a promising quantitative endogenous mRNA analysis tool for clinical applications.
研究领域:
分子生物学
·
纳米技术
·
生物医学工程
·
分析化学
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产品关联
DOI
PubMed
高影响因子
Analytical Methods
·
2025
·
IF 2.6
Changqing Du,Anran Li,Jinye Qiu,Jiarui Sun,Xiaokun Wang,Wei Xu,Maofeng Zhang,Dapeng Wang
Quantitative mRNA expression levels are essential for differential and clinical diagnoses. In this work, we present an apurinic/apyrimidinic endonuclease 1 (APE1)-assisted SERS sensing platform for rapid and ultrasensitive detection of TK1 mRNA. This platform utilizes a hairpin probe that contains a TK1 mRNA capture sequence along with an apurinic/apyrimidinic (AP) sites, which is specifically recognized and cleaved by APE1. Upon introduction of the target mRNA, hybridization occurs between the mRNA and the AP probe (HAP) within the hairpin structure, forming a doublestranded complex. APE1 then cleaves the HAP at the specific AP sites within the double-stranded complex, leading to a measurable change in the SERS intensity of the FAM-labeled HAP. Based on this principle, the developed SERS sensing platform demonstrates a highly linear response for TK1 mRNA detection across a wider range from 1 fM to 10 nM, with a detection limit (LOD) of 0.2 fM. Moreover, the SERS sensing platform shows great potential for the precise and quantitative detection of TK1 mRNA in human serum, which could be instrumental for mRNA-related research and the early clinical diagnosis of diseases.
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产品关联
DOI
PubMed
高影响因子
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