TY - JOUR
T1 - Non-invasive PTEN mRNA brain delivery effectively mitigates growth of orthotopic glioblastoma
AU - Liu, Yanjie
AU - Zhang, Dongya
AU - An, Yang
AU - Sun, Yajing
AU - Li, Jia
AU - Zheng, Meng
AU - Zou, Anne
AU - Shi, Bingyang
PY - 2023/4
Y1 - 2023/4
N2 - 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 (ABNPs@mRNA) 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 ABNPs@mRNA 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 ABNPs@mRNA 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 ABNPs@mRNA 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, ABNPs@mRNA 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.
AB - 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 (ABNPs@mRNA) 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 ABNPs@mRNA 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 ABNPs@mRNA 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 ABNPs@mRNA 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, ABNPs@mRNA 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.
KW - Non-invasive
KW - Blood brain barrier
KW - Glioblastoma
KW - PTEN gene
KW - Brain delivery
UR - http://www.scopus.com/inward/record.url?scp=85148540118&partnerID=8YFLogxK
U2 - 10.1016/j.nantod.2023.101790
DO - 10.1016/j.nantod.2023.101790
M3 - Article
SN - 1748-0132
VL - 49
SP - 1
EP - 12
JO - Nano Today
JF - Nano Today
M1 - 101790
ER -