Xiaoke Gao, Meng Zhang, Shiyang Du, Lixia Ma, Xiaohan Yao, Boao Xie, Jiajia Wan, Yuqiao Sheng, Bo Qin, Wenjing Deng, Ningjing Lei, Wentao Mo, Ming Wang, Zhijun Sun, Zhihai Qin, Fazhan Wang
{"title":"Engineering a spleen-selective mRNA-LNPs vaccine by decoupling the inflammation from cellular immunity-mediated cancer immunotherapy.","authors":"Xiaoke Gao, Meng Zhang, Shiyang Du, Lixia Ma, Xiaohan Yao, Boao Xie, Jiajia Wan, Yuqiao Sheng, Bo Qin, Wenjing Deng, Ningjing Lei, Wentao Mo, Ming Wang, Zhijun Sun, Zhihai Qin, Fazhan Wang","doi":"10.7150/thno.118976","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> mRNA vaccine-based cancer immunotherapy requires innate immune activation followed by potent cellular immunity. Vectors of lipid nanoparticles (LNPs) with proinflammatory properties activate the innate immune pathway, while excessive inflammatory response of mRNA-LNPs vaccine often results in systemic inflammation, compromising its therapeutic safety. <b>Methods:</b> Here, we engineered a spleen-selective mRNA-LNPs (mRNA-sLNPs) vaccine by decoupling the excessive inflammation from strong cellular immunity through ionizable lipids substituting for potent cancer immunotherapy. <b>Results:</b> The mRNA-sLNPs vaccine with reduced inflammation achieved superior mRNA translation in the spleen and enhanced antigen-specific cellular immune responses. Mechanistically, the optimized mRNA-sLNPs vaccine amplified lysosomal escape and boosted antigen presentation with moderate co-stimulatory molecule expression by mitigating TLR4/MyD88/NF-κB signaling and pro-inflammatory cytokine secretion. In therapeutic mouse models, the engineered mRNA vaccine significantly inhibited both the growth of subcutaneous B16F10-OVA melanomas and the development of lung metastases following intravenous injection of B16F10-OVA cells with augmented infiltration of CD4<sup>+</sup> and CD8<sup>+</sup> T cells in the tumor microenvironment. <b>Conclusion:</b> Our findings might redefine the design principles of mRNA-LNPs vaccine as diminishing the inflammation of LNPs does not compromise cellular immunity, offering a clinically translatable strategy to advance mRNA vaccines for cancer immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9643-9662"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486252/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.118976","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Rationale: mRNA vaccine-based cancer immunotherapy requires innate immune activation followed by potent cellular immunity. Vectors of lipid nanoparticles (LNPs) with proinflammatory properties activate the innate immune pathway, while excessive inflammatory response of mRNA-LNPs vaccine often results in systemic inflammation, compromising its therapeutic safety. Methods: Here, we engineered a spleen-selective mRNA-LNPs (mRNA-sLNPs) vaccine by decoupling the excessive inflammation from strong cellular immunity through ionizable lipids substituting for potent cancer immunotherapy. Results: The mRNA-sLNPs vaccine with reduced inflammation achieved superior mRNA translation in the spleen and enhanced antigen-specific cellular immune responses. Mechanistically, the optimized mRNA-sLNPs vaccine amplified lysosomal escape and boosted antigen presentation with moderate co-stimulatory molecule expression by mitigating TLR4/MyD88/NF-κB signaling and pro-inflammatory cytokine secretion. In therapeutic mouse models, the engineered mRNA vaccine significantly inhibited both the growth of subcutaneous B16F10-OVA melanomas and the development of lung metastases following intravenous injection of B16F10-OVA cells with augmented infiltration of CD4+ and CD8+ T cells in the tumor microenvironment. Conclusion: Our findings might redefine the design principles of mRNA-LNPs vaccine as diminishing the inflammation of LNPs does not compromise cellular immunity, offering a clinically translatable strategy to advance mRNA vaccines for cancer immunotherapy.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.