Engineering a spleen-selective mRNA-LNPs vaccine by decoupling the inflammation from cellular immunity-mediated cancer immunotherapy.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI:10.7150/thno.118976
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
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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.

通过将炎症与细胞免疫介导的癌症免疫治疗解耦,设计脾脏选择性mRNA-LNPs疫苗。
原理:基于mRNA疫苗的癌症免疫治疗需要先天免疫激活,然后是有效的细胞免疫。具有促炎特性的脂质纳米颗粒(LNPs)载体可激活先天免疫途径,而mRNA-LNPs疫苗的过度炎症反应往往导致全身炎症,影响其治疗安全性。方法:在这里,我们设计了一种脾脏选择性mRNA-LNPs (mRNA-sLNPs)疫苗,通过电离脂质取代强效癌症免疫治疗,将过度炎症与强细胞免疫解耦。结果:减少炎症的mRNA- slnps疫苗在脾脏中实现了优越的mRNA翻译,并增强了抗原特异性细胞免疫反应。机制上,优化后的mRNA-sLNPs疫苗通过减轻TLR4/MyD88/NF-κB信号传导和促炎细胞因子分泌,扩增溶酶体逃逸,促进抗原呈递,适度共刺激分子表达。在治疗性小鼠模型中,在静脉注射B16F10-OVA细胞并增强肿瘤微环境中CD4+和CD8+ T细胞的浸润后,工程化mRNA疫苗显著抑制皮下B16F10-OVA黑色素瘤的生长和肺转移的发展。结论:我们的研究结果可能重新定义mRNA-LNPs疫苗的设计原则,因为减少LNPs的炎症不会损害细胞免疫,为推进mRNA疫苗用于癌症免疫治疗提供了一种临床可翻译的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
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.
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