将工程细胞外囊泡作为溶酶体降解 PCSK9 的纳米海绵。

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Chen Wang, Xueying Zhou, Te Bu, Shuang Liang, Zhenzhen Hao, Mi Qu, Yang Liu, Mengying Wei, Changyang Xing, Guodong Yang, Lijun Yuan
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引用次数: 0

摘要

Proprotein convertase subtilisin/kexin type 9 (PCSK9)在低密度脂蛋白受体(LDLR)降解过程中起着至关重要的作用,因此抑制PCSK9成为治疗动脉粥样硬化的一种有吸引力的策略。本研究将细胞外囊泡(EVs)设计成纳米海绵,使其能有效吸附并将PCSK9送入溶酶体进行降解。简而言之,纳米海绵是用EGF-A/PTGFRN融合蛋白(PCSK9结合域EGF-A与前列腺素F2受体负调控因子的C端融合,前列腺素F2受体负调控因子的突变体LDLR具有更高的亲和力)修饰EV。经过修饰后,EVs 表面上显示了数百个 EGF-A,从而具备了高效吸附 PCSK9 的能力。这样,当纳米海绵被肝细胞内吞时,吸附的 PCSK9 就会被送入溶酶体降解,从而使内源性 LDLR 从降解中释放出来。在载脂蛋白E-/-小鼠模型中,尾静脉注射纳米海绵能够降解PCSK9,增加LDLR的表达,降低LDL-C水平,从而缓解动脉粥样硬化。总之,我们在此不仅开发了一种抑制 PCSK9 的新策略,还提出了一种用于疾病管理的吸附和降解循环蛋白的通用方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the degradation of the low-density lipoprotein receptor (LDLR), and PCSK9 inhibition emerges as an attractive strategy for atherosclerosis management. In this study, extracellular vesicles (EVs) were engineered to nanosponges, which could efficiently adsorb and deliver PCSK9 into lysosomes for degradation. Briefly, nanosponges were engineered by modifying EVs with EGF-A/PTGFRN fusion protein (PCSK9 binding domain EGF-A from the mutant LDLR with higher affinity was fused to the C terminus of prostaglandin F2 receptor negative regulator). The modification endowed the EVs with hundreds of EGF-As displayed on the surface, and thus the capacity to adsorb PCSK9 efficiently. The adsorbed PCSK9 would thus be delivered into lysosomes for degradation when the nanosponges were endocytosed by liver cells, thus releasing endogenous LDLR from degradation. In the ApoE-/- mouse model, tail vein-injected nanosponges were able to degrade PCSK9, increase LDLR expression, lower the LDL-C level, and thus alleviate atherosclerosis. In summary, here we not only develop a novel strategy for PCSK9 inhibition but we also propose a universal method for adsorption and degradation of circulating proteins for disease management.

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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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