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通过mRNA包裹的脂质纳米颗粒增强表观遗传调控可实现靶向抗炎控制。

Enhanced epigenetic modulation via mRNA-encapsulated lipid nanoparticles enables targeted anti-inflammatory control.

作者信息

Mokhtari Tahere, Taheri Mohammad N, Akhlaghi Sarah, Aryannejad Armin, Xiang Yuda, Mahajan Vineet, Keshavarz Kamyar, Kiani Amirreza, LoPresti Samuel, LeGraw Ryan, Whitehead Kathryn A, Kiani Samira

机构信息

Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

出版信息

bioRxiv. 2025 Feb 28:2025.02.24.639996. doi: 10.1101/2025.02.24.639996.

DOI:10.1101/2025.02.24.639996
PMID:40060445
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11888353/
Abstract

Temporal transcriptional modulation of immune-related genes offers powerful therapeutic potential for treating inflammatory diseases. Here, we introduce an enhanced zinc finger (ZF)-based transcriptional repressor delivered via lipid nanoparticles for controlling immune signaling pathways . By targeting Myd88, an essential adaptor molecule involved in immunity, our system demonstrates therapeutic efficacy against septicemia in C57BL/6J mice and improves repeated AAV administration by reducing antibody responses. This epigenetic engineering approach provides a platform for safe and efficient immunomodulation applicable across diseases caused by imbalanced inflammatory responses.

摘要

免疫相关基因的时间转录调控为治疗炎症性疾病提供了强大的治疗潜力。在此，我们引入了一种通过脂质纳米颗粒递送的增强型基于锌指（ZF）的转录抑制因子，用于控制免疫信号通路。通过靶向髓样分化因子88（Myd88），一种参与免疫的关键衔接分子，我们的系统在C57BL/6J小鼠中显示出对败血症的治疗效果，并通过降低抗体反应改善了反复腺相关病毒（AAV）给药。这种表观遗传工程方法为安全有效地免疫调节提供了一个平台，适用于由炎症反应失衡引起的各种疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74f7/11888353/d08315a5a849/nihpp-2025.02.24.639996v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74f7/11888353/016bef580a16/nihpp-2025.02.24.639996v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74f7/11888353/9b523b3ca9c3/nihpp-2025.02.24.639996v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74f7/11888353/d08315a5a849/nihpp-2025.02.24.639996v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74f7/11888353/016bef580a16/nihpp-2025.02.24.639996v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74f7/11888353/9b523b3ca9c3/nihpp-2025.02.24.639996v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74f7/11888353/d08315a5a849/nihpp-2025.02.24.639996v1-f0003.jpg

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Codon-optimization in gene therapy: promises, prospects and challenges.基因治疗中的密码子优化：前景、展望与挑战。
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Lipid nanoparticle structure and delivery route during pregnancy dictate mRNA potency, immunogenicity, and maternal and fetal outcomes.
脂质纳米颗粒的结构和在怀孕期间的输送途径决定了 mRNA 的效力、免疫原性以及母婴结局。
Proc Natl Acad Sci U S A. 2024 Mar 12;121(11):e2307810121. doi: 10.1073/pnas.2307810121. Epub 2024 Mar 4.
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Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer.腺相关病毒（AAV）载体的基因转移免疫原性。
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Recent Advances in Lipid Nanoparticles for Delivery of mRNA.用于递送mRNA的脂质纳米颗粒的最新进展
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Tolerogenic Nanovaccine for Prevention and Treatment of Autoimmune Encephalomyelitis.免疫耐受纳米疫苗防治自身免疫性脑脊髓炎。
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