AbstractLocal delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP).

摘要基于mRNA的免疫疗法的局部递送提供了一种有前途的途径，因为它能够产生特定的免疫调节蛋白，这些蛋白可以刺激免疫系统识别和消除癌细胞，同时限制全身暴露和毒性。在这里，我们开发并使用基于脂质的纳米颗粒（LNPs）在肿瘤内递送编码细胞因子白细胞介素（IL）-21和IL-7以及免疫刺激分子4-1BB配体（三重态LNP）的mRNA混合物。

IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking.

IL-21与IL-7和4-1BBL的协同作用导致肿瘤浸润性CD8+T细胞的频率及其产生颗粒酶B和IFN-γ的能力显着增加，从而导致肿瘤根除和长期免疫记忆的发展。从机制上讲，三联体LNP的功效取决于肿瘤引流淋巴结向肿瘤CD8+T细胞的运输。

Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer..

此外，我们强调了三联体LNP在雌性小鼠多种肿瘤模型中的治疗潜力及其对免疫检查点阻断的优越治疗效果。最终，这些免疫调节剂的表达与癌症患者更好的总体生存率相关。。

IntroductionTherapeutic mRNA is a versatile and precise tool that can be exploited against a wide range of diseases, including cancer1,2. mRNA encoding immunostimulatory proteins, such as cytokines and costimulatory molecules, can boost immune effector cells to target and eradicate cancer cells. Intratumoral administration of therapeutic mRNA increases the concentration of immunostimulatory proteins within the tumor microenvironment (TME), inducing potent anti-tumor responses in preclinical tumor models, while reducing systemic exposure and hence toxicity3,4,5,6.

引言治疗性mRNA是一种多功能且精确的工具，可用于治疗多种疾病，包括癌症1,2。编码免疫刺激蛋白（例如细胞因子和共刺激分子）的mRNA可以增强免疫效应细胞以靶向和根除癌细胞。肿瘤内施用治疗性mRNA可增加肿瘤微环境（TME）内免疫刺激蛋白的浓度，在临床前肿瘤模型中诱导有效的抗肿瘤反应，同时减少全身暴露，从而降低毒性3,4,5,6。

Nonetheless, poor translation efficiency of naked mRNA remains a challenge due to its instability, high susceptibility to degradation by ribonucleases, and limited cellular uptake7. The encapsulation of therapeutic mRNA in lipid-based nanoparticles (LNPs) can overcome these issues, improving its translation efficiency within the TME and overall therapeutic efficacy5,6,8,9.Interleukin (IL)−21, a member of the common γ-chain cytokine family, modulates diverse immune cell subsets, including T cells, B cells, natural killer (NK) cells, macrophages, monocytes, and dendritic cells (DCs)10.

尽管如此，裸mRNA的翻译效率差仍然是一个挑战，因为它不稳定，对核糖核酸酶降解的高度敏感性以及有限的细胞摄取7。将治疗性mRNA包封在基于脂质的纳米颗粒（LNPs）中可以克服这些问题，提高其在TME中的翻译效率和总体治疗效果5,6,8,9。白细胞介素（IL）-21是常见γ链细胞因子家族的成员，调节多种免疫细胞亚群，包括T细胞，B细胞，自然杀伤（NK）细胞，巨噬细胞，单核细胞和树突状细胞（DC）10。

IL-21 was shown to promote NK and T-cell proliferation and regulate their effector functions including their cytotoxic capacity and secretion of interferon (IFN)-γ, eliciting anti-tumor responses in multiple preclinical tumor models11,12,13,14,15,16. In these studies, either recombinant IL-2111,12,13,14 or oncolytic viruses armed with IL-2115,16 were used.

显示IL-21促进NK和T细胞增殖并调节其效应功能，包括其细胞毒性能力和干扰素（IFN）-γ的分泌，在多种临床前肿瘤模型中引发抗肿瘤反应11,12,13,14,15,16。在这些研究中，使用重组IL-2111,12,13,14或携带IL-2115,16的溶瘤病毒。

Recombinant IL-21 exhibits a short half-life of 0.2 h in mice17 and 2 h in humans18, which has limited its therapeutic efficacy in clinical trials19. On the other hand, the use of viral vectors is associated with the risk of insertional mutagenesis and the development of anti-vec.

重组IL-21在小鼠中表现出0.2小时的短半衰期17，在人类中表现出2小时的短半衰期18，这限制了其在临床试验中的治疗效果19。另一方面，病毒载体的使用与插入突变的风险和抗vec的发展有关。

Data availability

数据可用性

The CITE-seq raw data generated in this study has been deposited in the GEO database (NCBI) under accession code GSE249674. Survival analysis of cancer patients was performed using the survival analysis web-based tool KM plotter – immunotherapy [https://kmplot.com/analysis/index.php?p=service&cancer=immunotherapy].

本研究中产生的CITE-seq原始数据已保存在GEO数据库（NCBI）中，登录号为GSE249674。使用基于网络的生存分析工具KM绘图仪-免疫疗法对癌症患者进行生存分析[https://kmplot.com/analysis/index.php?p=service&cancer=immunotherapy]。

The remaining data are available within the Article, Supplementary Information or Source Data file.  Source data are provided with this paper..

其余数据可在文章，补充信息或源数据文件中找到。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank Nadia Abou, Constantinos Papadopoulos, Eleonora Omasta, Ellen Vaneetvelde, and Maité Schuurmans for administrative and technical assistance. We are thankful to the VIB single cell core for providing access to RNA sequencing technologies and the Flow Cytometry Core Facility of Vrije Universiteit Brussel for the use of the Symphony A3 Flow Cytometer.

下载参考文献致谢我们感谢Nadia Abou，Constantinos Papadopoulos，Eleonora Omasta，Ellen Vaneetvelde和MaitéSchuurmans提供的行政和技术援助。我们感谢VIB单细胞核心提供RNA测序技术的使用，感谢布鲁塞尔Vrije大学流式细胞仪核心设施使用Symphony A3流式细胞仪。

A.E.I.H., J.F., E.B., A.D., L.J., I.V., M.C., S.D.K. and F.L. are supported by a grant from VLAIO (Flanders innovation & entrepreneurship (HBC.2019.2737). J.F., E.B., L.J., I.V., M.C., M.E.S., R.S., S.D.K. and F.L. were supported by the EXPERT project, which has received Funding from the European Union’s Horizon 2020 research and innovation program under Grant Agreement No.

A、 E.I.H.，J.F.，E.B.，A.D.，L.J.，I.V.，M.C.，S.D.K.和F.L.得到了VLAIO的资助（法兰德斯创新与创业（HBC。2019.2737）。J、 F.，E.B.，L.J.，I.V.，M.C.，M.E.S.，R.S.，S.D.K.和F.L.得到了专家项目的支持，该项目已获得欧盟地平线2020研究与创新计划的资助。

825828. P.M.R.B, L.A., A.A.C. and A.G.P. are supported by predoctoral grants from FWO Vlaanderen (1154720 N, 11P1824N, 1169521 N, 1SH0424N). E.K and LAvG are funded by grants from the FWO and Vrije Universiteit Brussel. M.G. and B.G.D.G. are supported by grants from Stichting tegen kanker and Ghent University.

825828.P.M.R.B，L.A.，A.A.C.和A.G.P.得到了FWO Vlaanderen（1154720 N，11P1824N，1169521 N，1SH0424N）的博士前资助。E、 K和LAvG由FWO和布鲁塞尔弗里耶大学的资助。M、 G.和B.G.D.G.得到了Stichting tegen kanker和根特大学的资助。

F.C and L.F are supported by Vrije Universiteit Brussel. E.H. is supported by a postdoctoral grant from FWO Vlaanderen (12Y1922N). F.A.N is supported by the Fonds de la Recherche Scientifique FNRS (Belgium) Grants and Fellowships, S.D.S is supported by a postdoctoral grant from Stichting tegen kanker (2021-023).

F、 C和L.F得到了布鲁塞尔自由大学的支持。E、 H.得到了FWO Vlaanderen（12Y1922N）的博士后资助。F、 A.N得到了比利时科学研究基金会（Fonds de la Recherche Scientifique FNRS）的资助和研究金，S.D.S得到了Stichting tegen kanker（2021-023）的博士后资助。

D.L. is supported by grants from FWO, Kom op tegen Kanker, Stichting tegen kanker, VIB and Vrije Universiteit Brussel.Author informationAuthor notesThese authors contributed equally: Jessica Filtjens, Elisabeth Brabants.These authors jointly supervised this work: Florence Lambolez, Damya Laoui.Authors and AffiliationsLab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center .

D、 L.得到了FWO、Kom op tegen Kanker、Stichting tegen Kanker、VIB和布鲁塞尔自由大学的资助。作者信息作者注意到这些作者做出了同样的贡献：杰西卡·菲尔特金斯（JessicaFiltjens），伊丽莎白·布拉班茨（ElisabethBrabants）。这些作者共同监督了这项工作：佛罗伦萨·兰博雷斯（Florence Lambolez），达米亚·拉乌伊（Damya Laoui）。VIB中心树突状细胞生物学和癌症免疫治疗的作者和附属机构。

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PubMed Google ScholarContributionsConceptualization: A.E.I.H., S.D.K., F.L., D.L. Investigation: A.E.I.H., J.F., E.B., A.D., J.B., L.J., P.M.R.B., E.K., L.A., M.G., I.V., M.C., E.J.C., F.C., A.A.C., A.G.P., L.F., E.H., M.E.S., R.S., S.D. Formal analysis: A.E.I.H., J.F., E.B., D.K., E.K., P.L., M.G., L.Av.G.

PubMed谷歌学术贡献概念：A.E.I.H.，S.D.K.，F.L.，D.L.调查：A.E.I.H.，J.F.，E.B.，A.D.，J.B.，L.J.，P.M.R.B.，E.K.，L.A.，M.G.，I.V.，M.C.，E.J.C.，F.C.，A.A.C.，A.G.P.，L.F.，E.H.，M.E.S.，R.S.，S.D.正式分析：A.E.I.H.，J.F.，E.B.，D.K.，E.K.，P.L.，M.G.，L.Av。G。

Providing human samples: F.A.N. Visualization: A.E.I.H., J.F., D.K., B.G.D.G. Writing – original draft: A.E.I.H. Writing – review and editing: A.E.I.H., F.L., D.L. with input of all authors. Supervision: F.L., D.L. Funding acquisition: S.D.K., B.G.D.G., F.L., D.L.Corresponding authorsCorrespondence to.

提供人体样本：F.A.N.可视化：A.E.I.H.，J.F.，D.K.，B.G.D.G.写作-原稿：A.E.I.H.写作-审查和编辑：A.E.I.H.，F.L.，D.L.所有作者的投入。监督：F.L.，D.L。资金获取：S.D.K.，B.G.D.G.，F.L.，D.L。通讯作者通讯。

Florence Lambolez or Damya Laoui.Ethics declarations

佛罗伦萨·兰博雷斯或达米亚·拉乌伊。道德宣言

Competing interests

相互竞争的利益

J.F., E.B., S.D.K., and F.L. are employees of etherna. J.F., E.B., S.D.K., and F.L. have applied for a patent related to the study (Compositions and methods for delivery of agents to immune cells; WO2023118411A1). S.D.K. and B.G.D.G. have applied for a patent related to the ionizable lipids used in this work (Ionizable lipids; WO2022136641A1).

J、 F.，E.B.，S.D.K.和F.L.是etherna的员工。J、 F.，E.B.，S.D.K.和F.L.已经申请了与该研究相关的专利（用于向免疫细胞递送药剂的组合物和方法；WO2023118411A1）。S、 D.K.和B.G.D.G.已申请与本工作中使用的可电离脂质（可电离脂质；WO2022136641A1）相关的专利。

All other authors declare no potential conflicts of interest..

所有其他作者声明没有潜在的利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature Communications thanks Zhiliang Bai, Alvaro Teijeira, Xiaoyang Xu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

《自然通讯》感谢白志良、阿尔瓦罗·泰耶拉、徐晓阳和另一位匿名审稿人对这项工作的同行评审做出的贡献。可以获得同行评审文件。

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You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

根据本许可证，您无权共享源自本文或其部分的改编材料。本文中的图像或其他第三方材料包含在文章的知识共享许可证中，除非该材料的信用额度中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不受法律法规的许可或超出许可用途，则您需要直接获得版权所有者的许可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/..

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Reprints and permissionsAbout this articleCite this articleHamouda, A.E.I., Filtjens, J., Brabants, E. et al. Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity.

转载和许可本文引用本文Hamouda，A.E.I.，Filtjens，J.，Brabants，E。等人。肿瘤内递送编码IL-21，IL-7和4-1BBL的脂质纳米颗粒配制的mRNA诱导全身抗肿瘤免疫。

Nat Commun 15, 10635 (2024). https://doi.org/10.1038/s41467-024-54877-9Download citationReceived: 01 December 2023Accepted: 25 November 2024Published: 06 December 2024DOI: https://doi.org/10.1038/s41467-024-54877-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Nat Commun 1510635（2024）。https://doi.org/10.1038/s41467-024-54877-9Download引文接收日期：2023年12月1日接收日期：2024年11月25日发布日期：2024年12月6日OI：https://doi.org/10.1038/s41467-024-54877-9Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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