机构:[1]Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[2]Department of Experimental Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China四川省肿瘤医院[3]Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China外科中心头颈外科中心四川省肿瘤医院
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.
基金:
National Key Research and Development Program of China [2023YFC3403200]; The 1.3.5 Project for Disciplines of Excellence from West China Hospital, Sichuan University [ZYYC24009, ZYYC25007]; National Natural Science Foundation of China [82300113]; Sichuan Province Science and Tech-nology Support Program [2025YFHZ0088]
第一作者机构:[1]Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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通讯作者:
推荐引用方式(GB/T 7714):
Qiao Lijie,Fan Na,Zhang Yupei,et al.SitoC7A-modified lipid nanoparticles for integrated mRNA delivery and targeted STING activation[J].JOURNAL OF CONTROLLED RELEASE.2025,387:doi:10.1016/j.jconrel.2025.114238.
APA:
Qiao, Lijie,Fan, Na,Zhang, Yupei,Chen, Yuting,Qin, Shugang&Song, Xiangrong.(2025).SitoC7A-modified lipid nanoparticles for integrated mRNA delivery and targeted STING activation.JOURNAL OF CONTROLLED RELEASE,387,
MLA:
Qiao, Lijie,et al."SitoC7A-modified lipid nanoparticles for integrated mRNA delivery and targeted STING activation".JOURNAL OF CONTROLLED RELEASE 387.(2025)