张力素
PTEN公司
胶质瘤
癌症研究
信使核糖核酸
癌症
纳米医学
生物
医学
内科学
信号转导
细胞生物学
基因
PI3K/AKT/mTOR通路
生物化学
材料科学
纳米颗粒
纳米技术
作者
Yanjie Liu,Dongya Zhang,Shaoping Ji,Yajing Sun,Jia Li,Meng Zheng,Yan Zou,Bingyang Shi
出处
期刊:Nano Today
[Elsevier]
日期:2023-04-01
卷期号:49: 101790-101790
被引量:24
标识
DOI:10.1016/j.nantod.2023.101790
摘要
Messenger RNA (mRNA) based gene therapy holds great promise for treating various brain-related disorders including brain cancer. However, mRNA instability, inability to pass the blood-brain barrier (BBB) and lack of tumour targeting, hindering the further application of mRNA in brain disease therapy. Here we designed a new mRNA nanomedicine ([email protected]) and demonstrated that it could effectively address the above challenges by combining three distinct design strategies: ApoE peptide based "two birds, one stone" targeting, cell membrane based biomimetic cloaking and tumour microenvironment responsive controlled drug release. To effectively target to glioblastoma (GBM), we loaded [email protected] with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) mRNA, a tumour suppressor that is mutated or inactive in 20–40% of GBM. Loss of PTEN activity in GBM patients correlates with therapeutic resistance, oncogenesis and poor prognosis. Together, our three design elements enabled [email protected] to deliver a maximum PTEN mRNA concentration of 7.22% injection dose (ID)/g in brain tumour tissue. In the orthotopic GBM mouse models (U87MG and patient-derived CSC2 GSCs xenograft), treatment with [email protected] resulted in a remarkable extension of median survival time relative to mice receiving PBS (49 d versus 23 d in U87MG and 40 d versus 23 d in CSC2 model). Importantly, [email protected] nanomedicine caused negligible side effects in major organs including liver and kidney. Considering the stability, safety, non-invasive brain delivery and GBM inhibition efficacy, our new mRNA nanomedicine may unlock a new avenue for mRNA application in GBM inhibition and beyond.
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