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Author Spotlight: Exploring Macrophage Immunometabolism Through Lentiviral Vector-Mediated Gene Manipulation
Published on: February 16, 2024
Liposome-lentivirus for miRNA therapy with molecular mechanism study
Fen Sun1,2, Huaqing Chen2,3, Xiaoyong Dai2,4
1Institute of Animal Sciences and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, 250000, China.
Background:
Cancer stem cells (CSCs) play a vital role in the occurrence, maintenance, and recurrence of solid tumors. Although, miR-145-5p can inhibit CSCs survival, poor understanding of the underlying mechanisms hamperes further therapeutic optimization for patients. Lentivirus with remarkable transduction efficiency is the most commonly used RNA carrier in research, but has shown limited tumor-targeting capability.
Methods:
We have applied liposome to decorate lentivirus surface thereby yielding liposome-lentivirus hybrid-based carriers, termed miR-145-5p-lentivirus nanoliposome (MRL145), and systematically analyzed their potential therapeutic effects on liver CSCs (LCSCs).
Results:
MRL145 exhibited high delivery efficiency and potent anti-tumor efficacy under in vitro and in vivo. Mechanistically, the overexpressed miR-145-5p can significantly suppress the self-renewal, migration, and invasion abilities of LCSCs by targeting Collagen Type IV Alpha 3 Chain (COL4A3). Importantly, COL4A3 can promote phosphorylating GSK-3β at ser 9 (p-GSK-3β S9) to inactivate GSK3β, and facilitate translocation of β-catenin into the nucleus to activate the Wnt/β-catenin pathway, thereby promoting self-renewal, migration, and invasion of LCSCs. Interestingly, COL4A3 could attenuate the cellular autophagy through modulating GSK3β/Gli3/VMP1 axis to promote self-renewal, migration, and invasion of LCSCs.
Conclusions:
These findings provide new insights in mode of action of miR-145-5p in LCSCs therapy and indicates that liposome-virus hybrid carriers hold great promise in miRNA delivery.
Insights
This study introduces miR-145-5p-lentivirus nanoliposomes (MRL145) for liver cancer stem cell (LCSC) therapy. MRL145 effectively suppresses LCSC self-renewal and invasion by targeting COL4A3, offering a promising new delivery method.
Area of Science:
- Oncology
- Molecular Biology
- Nanotechnology
Background:
- Cancer stem cells (CSCs) are crucial in solid tumor development and recurrence.
- MicroRNA-145-5p (miR-145-5p) inhibits CSC survival, but its therapeutic mechanisms require further elucidation.
- Conventional lentivirus carriers have limited tumor-targeting capabilities.
Purpose of the Study:
- To develop and evaluate novel liposome-lentivirus hybrid nanocarriers for enhanced delivery of miR-145-5p to liver CSCs (LCSCs).
- To investigate the therapeutic efficacy and underlying molecular mechanisms of miR-145-5p delivery in LCSCs.
Main Methods:
- Construction of liposome-lentivirus hybrid nanocarriers (MRL145) for miR-145-5p delivery.
- Systematic analysis of MRL145's therapeutic effects on LCSCs in vitro and in vivo.
- Mechanistic studies involving target gene identification (COL4A3) and pathway analysis (Wnt/β-catenin, autophagy).
Main Results:
- MRL145 demonstrated high delivery efficiency and potent anti-tumor efficacy against LCSCs.
- Overexpressed miR-145-5p significantly suppressed LCSC self-renewal, migration, and invasion by targeting Collagen Type IV Alpha 3 Chain (COL4A3).
- COL4A3 was found to promote LCSC progression by inactivating GSK3β, activating the Wnt/β-catenin pathway, and attenuating autophagy via the GSK3β/Gli3/VMP1 axis.
Conclusions:
- The study provides novel insights into the anti-CSC action of miR-145-5p.
- Liposome-virus hybrid nanocarriers represent a promising platform for miRNA delivery in cancer therapy.
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