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限制内体损伤传感可以减少由脂质纳米粒子内体逃逸引发的炎症

Serena Omo-Lamai¹, Yufei Wang², Manthan N Patel²

¹Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.

Nature nanotechnology

|August 11, 2025

概括

脂质纳米颗粒 (LNPs) 通过内体损伤引起炎症,触发了 galectin 反应. 抑制胆素或使用ESCRT可修复脂质可以减少LNP炎症,从而使治疗性mRNA在炎症性疾病中使用成为可能.

科学领域:

生物技术是生物技术.
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

脂质纳米颗粒 (LNP) 是RNA传递的关键,但会导致严重的炎症.
内体逃逸,对于RNA表达至关重要,也会损害内体膜,启动炎症途径.

研究的目的:

研究LNP诱导炎症的机制.
确定减少LNP相关炎症的策略,以获得更安全的RNA疗法.
探索质素和ESCRT途径在LNP炎症中的作用.

主要方法:

研究了LNP诱导的内体细胞膜损伤和随后的炎症.
在实验室和体内评估了细胞结合物加勒素在中介LNP炎症中的作用.
开发并测试了形成较小,ESCRT可修复的内体孔的可离子化脂质.
在使用修改后的LNP策略的炎症性疾病模型中评估了治疗性mRNA输送.

主要成果:

由LNP诱导的内分体膜损伤通过 galectin 识别触发炎症.
抑制加勒素有效地消除了与LNP相关的炎症.
特定的可电离性脂质可以创建可修复的内体孔,从而使高mRNA表达与减少炎症.
盖莱克抑制或ESCRT招募脂质有助于治疗炎症疾病的mRNA治疗.

结论:

由LNP诱导的炎症是通过 galectin 感知内体膜损伤的介导.
向胆素或利用ESCRT招募脂质是开发非炎症性LNP的可行策略.
这些进展为更安全,更有效的基于RNA的炎症疗法铺平了道路.

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