Molecular Biomedicine
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2025
·Vol. 6
·期 1
·1-14
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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
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疫苗学
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DOI
PubMed
高影响因子
IMMUNOLOGIC RESEARCH
·
2023
·Vol. 71
·期 3
·356-372
·
IF 4.4
Lamprinou Malamatenia,Sachinidis Athanasios,Stamoula Eleni,Vavilis Theofanis,Papazisis Georgios
COVID-19 is an infectious disease caused by a single-stranded RNA (ssRNA) virus, known as SARS-CoV-2. The disease, since its first outbreak in Wuhan, China, in December 2019, has led to a global pandemic. The pharmaceutical industry has developed several vaccines, of different vector technologies, against the virus. Of note, among these vaccines, seven have been fully approved by WHO. However, despite the benefits of COVID-19 vaccination, some rare adverse effects have been reported and have been associated with the use of the vaccines developed against SARS-CoV-2, especially those based on mRNA and non-replicating viral vector technology. Rare adverse events reported include allergic and anaphylactic reactions, thrombosis and thrombocytopenia, myocarditis, Bell’s palsy, transient myelitis, Guillen-Barre syndrome, recurrences of herpes-zoster, autoimmunity flares, epilepsy, and tachycardia. In this review, we discuss the potential molecular mechanisms leading to these rare adverse events of interest and we also attempt an association with the various vaccine components and platforms. A better understanding of the underlying mechanisms, according to which the vaccines cause side effects, in conjunction with the identification of the vaccine components and/or platforms that are responsible for these reactions, in terms of pharmacovigilance, could probably enable the improvement of future vaccines against COVID-19 and/or even other pathological conditions.
研究领域:
免疫学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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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
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免疫学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
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2025
·
IF 12
Jingjing Zhang,Chao Li,Yuheng Liu,Rui Liao,Dian He,Lifeng Xu,Tingting Chen,Qin Xiao,Mingxing Luo,Yang Chen,Yali Li,Huaxing Zhu,Joseph Rosenecker,Xiaoyan Ding,Shuchen Pei,Shan Guan
The development of mucosal mRNA vaccines is promising but extremely challenging. Major efforts have been focused on optimizing delivery systems, whereas it is still unknown whether the intrinsic quality of mRNA components significantly impacts the potency of airway inoculated mRNA vaccines. Here, we systematically demonstrate mucosal mRNA vaccine requires higher standards of purification and tailor-designed sequence to fulfil its potency compared to parenteral-route inoculated counterpart. Double-stranded RNA (dsRNA) contaminants are prone to trigger innate immune response in the airway that activates the mRNA degradation mechanism, thereby diminishing the mRNA expression and subsequent antigen-specific immune responses. To address these challenges, we developed a strategy that combines optimized untranslated regions (UTRs) screened from endogenous genes of pulmonary cells with affinity chromatography-based purification which effectively removed dsRNA contaminants. The optimized mRNA administered via airway route not only demonstrated superior protein expression (30-fold increase) and reduced inflammation in the lung, but also promoted robust immunity comprising significantly elevated systemic, cellular, and mucosal immune responses, which was in stark contrast to intramuscular injected counterpart that displays less pronounced benefits. Our findings offer new insights into the development of mucosal mRNA therapeutics from an overlooked but crucial perspective of optimizing mRNA components.
研究领域:
免疫学
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分子生物学
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疫苗开发
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Xiaoya Guo,Zhiyu Yang,Zhaopei Guo,Huiyan Lai,Hanyu Meng,Meng Meng,Tong Li,Zhen Li,Jie Chen,Yuanji Feng,Xuan Pang,Huayu Tian,Xuesi Chen
The development of mRNA delivery carriers with innate immune stimulation functions has emerged as a focal point in the field of mRNA vaccines. Nonetheless, the expression of mRNA in specific sites and innate immune stimulation at specific sites are prerequisites for ensuring the safety of mRNA vaccines. Based on the synthetic PEIRs carriers library, this study identifies an innovative mRNA delivery carrier named POctS with the following characteristics: 1) simultaneously possessing high mRNA delivery efficiency and stimulator of interferon genes (STING) stimulation function. 2) Leveraging the distinctive site-specific delivery capabilities of POctS, the expression of mRNA at specific sites and the activation of innate immune responses at designated sites are achieved, minimizing formulation toxicity and maximizing the vaccine performance. 3) Tailoring two types of mRNA vaccines based on POctS according to the immune infiltration status of different types of tumors. Briefly, POctS-loading ovalbumin (OVA) mRNA as a tumor antigen vaccine achieves the prevention and treatment of melanoma in mice. Further, POctS-loading mixed lineage kinase domain-like protein (MLKL) mRNA as an in situ tumor vaccine effectively treats orthotopic pancreatic cancer in mice. This delivery carrier offers a feasible mRNA vaccine-based immunotherapy strategy for various types of tumors.
研究领域:
分子生物学
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免疫学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
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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
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免疫学
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生物医学工程
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分子成像
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疫苗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-12
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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
COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
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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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
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IF 6.7
Feifan Yin,Murilege Chao,Jinhua Chen,Yanheng Yao,Miao He,Qiufeng Wang,Wenting Cheng,Yongliang Cai,Zhongyun Wang,Yang Xiang
mRNA vaccines have been developed as a captivating and highly prospective avenue for the advancement of immunotherapy. With the advancement of antitumor mRNA vaccines into clinical trials, it is important to monitor the levels of nucleic acid drugs. In this study, we have engineered a new biosensor for melanoma-associated antigen mRNA vaccines utilizing an adjustable structure MNAzyme (ASM) activated by an entropy-driven circuit (EDC). The EDC process is specifically triggered by the target mRNA through the exposed toehold, achieving initial amplification. As a result of proximity effects facilitated by the EDC products, ASM is successfully assembled and activated by undergoing conformational transformation because of rational sequence design, continuously cleaving the fluorescence reporter and realizing the second round of signal amplification. Compared with conventional DNAzyme, ASM can effectively reduce signal leakage and concurrently preserve cleavage efficiency, benefiting from the stable presence of a stem-loop hairpin and an adjustable molecular switch. Moreover, composed only of DNA with highly integrated sequences, this method could realize detection in an enzyme-free, one-step, and one-pot detection manner. Finally, EDC-ASM demonstrates high programmability, excellent specificity, and sensitivity in nucleic acid detection, providing a novel strategy for the study of antitumor mRNA vaccines.
研究领域:
分子生物学
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生物传感
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肿瘤免疫治疗
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核酸分析
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转化医学
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药物监测
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产品关联
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
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免疫学
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药学
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生物技术
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Yu Han,Kai Zhang,Ning Xin,Xintao Gao,Guohua Ma,Jingtong An,Yantao Li
Despite recent advancements in lipid nanoparticles (LNPs)-based messenger RNA (mRNA) delivery, significant challenges persist in the structural optimization and functional modulation of their components for cancer immunotherapy, particularly regarding inadequate organ-specific targeting, and insufficient immune activation. Notably, metal ions have demonstrated emerging immunomodulatory potential, yet their coordinated self-assembly within LNPs as adjuvants to enhance the immunotherapeutic efficacy remains largely unexplored. To address these limitations, we combine newly designed imidazole-based LNPs with functional metal ions (Zn 2+ ) to develop novel Zn-coordinated LNP-based mRNA vaccines. A total of 48 imidazole-based ionizable lipids were designed and synthesized, among which C2–13 LNPs emerged as the top-performing formulation in terms of transfection efficiency. By innovatively incorporating Zn 2+ into C2–13 LNPs via coordination interaction, we further developed the novel metal-coordinated mRNA delivery systems, referred to as Zn-C2–13 LNPs. Compared to their non-metal counterparts, Zn-C2–13 LNPs exhibited markedly improved transfection efficiency and antigen presentation in vitro . Impressively, the synergistic effect of the optimized LNP formulation and Zn 2+ in the Zn-C2–13/mOVA systems (Zn-C2–13 LNPs loading ovalbumin mRNA) resulted in superior spleen-selective expression and immune response, significantly boosting the efficacy of cancer immunotherapy in the B16F10 ovalbumin-expressing (B16F10-OVA) melanoma tumor model. Collectively, this novel metal-coordinated LNPs improve specific organ targeting and immune responses, presenting a promising strategy to advance mRNA vaccine-based cancer immunotherapy.
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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分子生物学
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转化医学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Lele Gong,Yuanyuan Zhang,Lele Wang,Xuyang Zhao,Lucai Wang,Xiangqi Qiu,Xilong Yang,Wenhui Zhu,Lijie Lv,Yunzhe Kang,Yanan Wu,Angke Zhang,Yongkun Du,Xuannian Wang,Gaiping Zhang,Aijun Sun,Guoqing Zhuang
The African swine fever virus (ASFV) continues to pose significant economic and pandemic risks. Consequently, discovering new, efficient vaccines is crucial. Messenger RNA (mRNA) vaccines have emerged as promising candidates, providing minimal risk of insertional mutagenesis, high safety profiles, effectiveness, rapid scalability in production, and cost-effectiveness. In this study, we have developed an ASF p30 mRNA vaccine candidate (mRNA/Man-LNP) employing mannose-modified lipid nanoparticles (LNPs). The mRNA/Man-LNP exhibited effective antigen presentation and facilitated dendritic cells (DCs) maturation. Notably, it elicited strong IgG titers and activated CD4 + and CD8 + T-cells in immunized mice, all while adhering to stringent biosafety standards. This investigation demonstrates that mRNA/Man-LNP can trigger both humoral and cellular immune responses, suggesting its potential as a potent and promising vaccine candidate for controlling African swine fever (ASF).
研究领域:
兽医学
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免疫学
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分子生物学
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病毒学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）