Lipid nanoparticle mediated delivery of Anti-CD19 CAR mRNA to umbilical blood cord NK cells for targeting CD19⁺ primary B-ALL cells

IF 3 4区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Current Research in Translational Medicine Pub Date : 2026-01-01 Epub Date: 2025-12-17 DOI:10.1016/j.retram.2025.103563

Hossein Salehi-Shadkami , Mosslim Sedghi , Shima Tavoosi , Masoumeh Alimohammadi , Reza Alimohammadi , Maryam Barkhordar , Ahmadreza Mofayezi , Mohammad Sadra Modaresi , Mohammad Vaezi , Somaye Dehghanizadeh , Mohammad Ahmadvand , Vahid Khoddami

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Abstract

Chimeric antigen receptor natural killer (CAR-NK) cell therapy is recognized as a promising modality for the treatment of hematologic malignancies, particularly B-cell malignancies. In this study, we developed “off-the-shelf” anti-CD19 CAR-NK cells using anti-CD19 CAR mRNAs formulated in proprietary ionizable lipid nanoparticles (LNPs). The efficiency of mRNA-LNP delivery into umbilical cord blood (UCB)-derived NK cells and primary T cells was evaluated in an in vitro setting, demonstrating superior delivery efficiency in NK cells. Further investigation showed a probable role for an endocytic mechanism, macropinocytosis, in efficient transfection of NK cells with LNPs. Nevertheless, CAR-NK cells generated through this mRNA-LNP platform exhibited significantly enhanced cytotoxicity against CD19⁺ target cells, such as EGFP⁺Raji stable cell line and primary malignant B cells derived from refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL) patients. These findings highlight the promise of the mRNA-LNP platform in advancing CAR-NK therapies against B-cell malignancies.

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脂质纳米颗粒介导的抗CD19 CAR mRNA递送至脐带血NK细胞靶向CD19 +原代B-ALL细胞。

嵌合抗原受体自然杀伤（CAR-NK）细胞疗法被认为是治疗血液系统恶性肿瘤，特别是b细胞恶性肿瘤的一种有前途的方式。在这项研究中，我们使用专有的可电离脂质纳米颗粒（LNPs）配制的抗cd19 CAR- nk mrna开发了“现成的”抗cd19 CAR- nk细胞。在体外环境中评估mRNA-LNP在脐带血（UCB）来源的NK细胞和原代T细胞中的递送效率，显示出在NK细胞中的优越递送效率。进一步的研究表明，在LNPs有效转染NK细胞中，内吞机制巨噬作用可能起作用。然而，通过mRNA-LNP平台生成的CAR-NK细胞对CD19+靶细胞（如EGFP+Raji稳定细胞系和来自难治性/复发性B细胞急性淋巴细胞白血病（B- all）患者的原发性恶性B细胞）表现出显著增强的细胞毒性。这些发现突出了mRNA-LNP平台在推进CAR-NK治疗b细胞恶性肿瘤方面的前景。

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

Current Research in Translational Medicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

7.00

自引率

4.90%

发文量

审稿时长

45 days

期刊介绍： Current Research in Translational Medicine is a peer-reviewed journal, publishing worldwide clinical and basic research in the field of hematology, immunology, infectiology, hematopoietic cell transplantation, and cellular and gene therapy. The journal considers for publication English-language editorials, original articles, reviews, and short reports including case-reports. Contributions are intended to draw attention to experimental medicine and translational research. Current Research in Translational Medicine periodically publishes thematic issues and is indexed in all major international databases (2017 Impact Factor is 1.9). Core areas covered in Current Research in Translational Medicine are: Hematology, Immunology, Infectiology, Hematopoietic, Cell Transplantation, Cellular and Gene Therapy.