In vivo reprogramming of cytotoxic effector CD8 T cells via fractalkine-conjugated mRNA-LNPs.

IF 16.3 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2026-05-08 DOI:10.1126/sciimmunol.aec3436

Angela R Corrigan, Shin Foong Ngiow, Maura Statzu, Amie Albertus, M Betina Pampena, Jayme M L Nordin, Stephen D Carro, Justin Harper, Rachelle L Stammen, Jennifer Wood, Houping Ni, Justin Su, Marziyeh Hajialyani, Vladimir V Shuvaev, Victor Alcalde, Mohammed-Alkhatim A Ali, Jacob T Hamilton, Rajesvaran Ramalingam, Vincent H Wu, Mirko Paiardini, Drew Weissman, E John Wherry, Edward F Kreider, Michael R Betts

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引用次数: 0

Abstract

Selective in vivo reprogramming of cytotoxic effector CD8 T (T_eff) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNPs) can specifically target and deliver mRNA to CX3CR1⁺ T_eff cells in vitro and in vivo. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of blood and splenic T_eff cells. In addition, delivery of IL-2-encoding mRNA and human CD62L-encoding mRNA to mouse T_eff cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood T_eff cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood T_eff cells and detection of human CD62L⁺ T_eff cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of T_eff cells.

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通过分形因子偶联mRNA-LNPs在体内重编程细胞毒性效应CD8 T细胞。

细胞毒性效应CD8 T （Teff）细胞的选择性体内重编程作为一种治疗工具具有巨大的前景，但尚未完成。在这里，我们证明了分形因子共轭mRNA脂质纳米颗粒（mRNA- lnps）可以在体外和体内特异性靶向并传递mRNA到CX3CR1+ Teff细胞。在小鼠中，fractalkin -conjugated mRNA-LNPs靶向高达95%的血液和脾脏Teff细胞。此外，将编码IL-2的mRNA和编码人CD62L的mRNA传递到小鼠Teff细胞，使外源性IL-2分泌和CD62L表达强劲。在恒河猴中，分形因子结合的mRNA- lnps靶向高达~100%的外周血Teff细胞，传递编码人CD62L的mRNA可使外周血Teff细胞表面表达人CD62L，并在淋巴组织中检测到人CD62L+ Teff细胞。总的来说，这些数据证明了基于天然受体配体靶向mRNA-LNPs在Teff细胞快速、有效和短暂的体内修饰方面的潜力。

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

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.