Liposome-lentivirus for miRNA therapy with molecular mechanism study

• Published in: Journal of nanobiotechnology Vol. 22; no. 1; pp. 329 - 15
• Main Authors: Sun, Fen, Chen, Huaqing, Dai, Xiaoyong, Hou, Yibo, Li, Jing, Zhang, Yinghe, Huang, Laiqiang, Guo, Bing, Yang, Dongye
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 10.06.2024; BioMed Central; BMC
• Subjects: Animals; Autophagy; beta Catenin - metabolism; Cancer; Care and treatment; Cell Line, Tumor; Cell Movement; COL4A3; Collagen; Dosage and administration; Drug delivery systems; Drugs; Gene therapy; Glycogen Synthase Kinase 3 beta - metabolism; GSK3β/Wnt/β-catenin; Health aspects; Humans; Innovations; LCSCs; Lentivirus; Lentivirus - genetics; Liposomes; Liposomes - chemistry; Liver; Liver Neoplasms - therapy; Methods; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miR-145-5p; Neoplastic Stem Cells - metabolism; Physiological aspects; Stem cells; Tumors; Vehicles; Wnt Signaling Pathway; China; LCSCs; Autophagy; GSK3β/Wnt/β-catenin; COL4A3; miR-145-5p
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-024-02534-0

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. 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). 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. 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.