期刊
ACS NANO
卷 15, 期 11, 页码 18327-18346出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c07587
关键词
extracellular vesicles; cxcr4; microfluidics; blood brain barrier; microRNA; cancer therapy
类别
资金
- Gary Glazer-GE Fund (Department of Radiology, Stanford University)
- National Institutes of Health [R01CA209888, R21EB022298]
- NIH [S10OD023518-01A1, 200-BFFL-S]
A scalable microfluidic platform was developed to load therapeutic miRNAs and drugs into EVs while controlling their size, leading to improved treatment outcomes in orthotopic GBM mouse models. The engineered mpEVs demonstrated efficient delivery of miRNAs and drugs to GBM cells, resulting in tumor regression and increased survival rates in mice, showing potential for clinical translation in GBM therapy.
Extracellular vesicles (EVs), including exosomes and microvesicles derived from different cell sources, are used as promising nanovesicles for delivering therapeutic microRNAs (miRNAs) and drugs in cancer therapy. However, their clinical translation is limited by the quantity, size heterogeneity, and drug or small RNA loading efficiency. Herein, we developed a scalable microfluidic platform that can load therapeutic miRNAs (antimiRNA-21 and miRNA-100) and drugs while controlling the size of microfluidically processed EVs (mpEVs) using a pressure-based disruption and reconstitution process. We prepared mpEVs of optimal size using microvesicles isolated from neural stem cells engineered to overexpress CXCR4 receptor and characterized them for charge and miRNA loading efficiency. Since the delivery of therapeutic miRNAs to brain cancer is limited by the blood-brain barrier (BBB), we adopted intranasal administration of miRNA-loaded CXCR4-engineered mpEVs in orthotopic GBM mouse models and observed a consistent pattern of mpEVs trafficking across the nasal epithelia, bypassing the BBB into the intracranial compartment. In addition, the CXCR4-engineered mpEVs manifested selective tropism toward GBMs by stromal-derived factor-1 chemotaxis to deliver their miRNA cargo. The delivered miRNAs sensitized GBM cells to temozolomide, resulting in prominent tumor regression, and improved the overall survival of mice. A simple and efficient approach of packaging miRNAs in mpEVs using microfluidics, combined with a noninvasive nose-to-brain delivery route presents far-reaching potential opportunities to improve GBM therapy in clinical practice.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据