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双开关 pHLIP 系统能够选择性富集循环肿瘤微环境衍生的细胞外囊泡。

A double-switch pHLIP system enables selective enrichment of circulating tumor microenvironment-derived extracellular vesicles.

机构信息

State Key Laboratory of Medicinal Chemical Biology, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China.

出版信息

Proc Natl Acad Sci U S A. 2023 Jan 10;120(2):e2214912120. doi: 10.1073/pnas.2214912120. Epub 2023 Jan 3.

DOI:10.1073/pnas.2214912120
PMID:36595702
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9926244/
Abstract

Circulating tumor microenvironment-derived extracellular vesicles (cTME-EVs) are gaining considerable traction in cancer research and liquid biopsy. However, the study of cTME-EVs is largely limited by the dearth of a general isolation technique to selectively enrich cTME-EVs from biological fluids for downstream analysis. In this work, we broke through this dilemma by presenting a double-switch pH-low insertion peptide (D-S pHLIP) system to exclusively harvest cTME-EVs from the blood serum of tumor mouse models. This D-S pHLIP system consists of a highly sensitive pH-driven conformational switch (pa ≈ 6.8) that allows specific installation of D-S pHLIP on the EV membranes in TME (pH 6.5 to 6.8) and a unique hook-like switch to "lock" the peptide securely on the cTME-EVs during the systemic circulation. The D-S pHLIP-anchored cTME-EVs were magnetically enriched and then analyzed with high-resolution messenger RNA sequencing, by which more than 18 times the number of TME-related differentially expressed genes and 10 times the number of hub genes were identified, compared with those achieved by the gold-standard ultracentrifugation. This work could revolutionize basic TME research as well as clinical liquid biopsy for cancer.

摘要

循环肿瘤微环境衍生的细胞外囊泡（cTME-EVs）在癌症研究和液体活检中受到了广泛关注。然而，由于缺乏一种通用的分离技术来从生物体液中选择性富集 cTME-EVs 进行下游分析，因此对 cTME-EVs 的研究在很大程度上受到了限制。在这项工作中，我们通过提出一种双开关 pH 低插入肽（D-S pHLIP）系统来从肿瘤小鼠模型的血清中专门收获 cTME-EVs，从而突破了这一困境。该 D-S pHLIP 系统由一个高度敏感的 pH 驱动构象开关（pA ≈ 6.8）组成，该开关允许 D-S pHLIP 在 TME 中（pH 6.5 至 6.8）特异性地安装在 EV 膜上，以及一个独特的钩状开关，用于在系统循环过程中将肽“锁定”在 cTME-EVs 上。D-S pHLIP 锚定的 cTME-EVs 被磁性富集，然后进行高分辨率信使 RNA 测序分析，与超离心法相比，该方法鉴定出了超过 18 倍的与 TME 相关的差异表达基因和 10 倍的枢纽基因。这项工作可能会彻底改变癌症的基础 TME 研究和临床液体活检。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/a950fd6b19d2/pnas.2214912120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/ee78b91e0d8e/pnas.2214912120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/3c7b422be25e/pnas.2214912120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/23aa90804dd7/pnas.2214912120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/23ce8215cdb4/pnas.2214912120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/a950fd6b19d2/pnas.2214912120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/ee78b91e0d8e/pnas.2214912120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/3c7b422be25e/pnas.2214912120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/23aa90804dd7/pnas.2214912120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/23ce8215cdb4/pnas.2214912120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a22/9926244/a950fd6b19d2/pnas.2214912120fig05.jpg

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