Engineered extracellular vesicles mediated CRISPR-induced deficiency of IQGAP1/FOXM1 reverses sorafenib resistance in HCC by suppressing cancer stem cells

• Published in: Journal of nanobiotechnology 2023-05, Vol.21 (1), p.154-154, Article 154
• Main Authors: He, Cong, Jaffar Ali, Doulathunnisa, Qi, Yuhua, Li, Yumin, Sun, Beicheng, Liu, Rui, Sun, Bo, Xiao, Zhongdang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Antibodies; Anticancer properties; Cancer; cancer stem cells; Carcinoma, Hepatocellular - metabolism; Cell interactions; Cell Line, Tumor; Cell self-renewal; CRISPR; CRISPR/Cas9; Drug resistance; Drug therapy; Epithelial cells; Epithelium; Extracellular vesicles; Extracellular Vesicles - metabolism; Forkhead Box Protein M1 - metabolism; Genomes; Glypicans - metabolism; Hepatocytes; Hepatoma; Homing behavior; Humans; IQGAP1 protein; Liver cancer; Liver Neoplasms - metabolism; Medical prognosis; Neoplastic Stem Cells; Particle size; Phosphatidylinositol 3-Kinases - metabolism; Prevention; Proteins; Sorafenib - pharmacology; sorafenib resistance; Stem cells; Survival analysis; Vesicles
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-023-01902-6

Sorafenib resistance poses therapeutic challenges in HCC treatment, in which cancer stem cells (CSCs) plays a crucial role. CRISPR/Cas9 can be utilized as a potential technique to overcome the drug resistance. However, a safe, efficient and target specific delivery of this platform remains challenging. Extracellular vesicles (EVs), the active components of cell to cell communication, hold promising benefits as delivery platform. Herein we report the normal epithelial cell -derived EVs engineered with HN3(HLC9-EVs) show competing tumor targeting ability. Anchoring HN3 to the membrane of the EVs through LAMP2, drastically increased the specific homing of HLC9-EVs to GPC3 Huh-7 cancer cells rather than co-cultured GPC3 LO2 cells. Combination therapy of HCC with sorafenib and HLC9-EVs containing sgIF to silence IQGAP1 (protein responsible for reactivation of Akt/PI3K signaling in sorafenib resistance) and FOXM1 (self-renewal transcription factor in CSCs attributed to sorafenib resistance), exhibited effective synergistic anti-cancer effect both in vitro and in vivo. Our results also showed that disruption of IQGAP1/FOXM1 resulted in the reduction of CD133 population that contribute to the stemness of liver cancer cells. By reversing sorafenib resistance using combination therapeutic approach with engineered EVs encapsulated CRISPR/Cas9 and sorafenib, our study foreshadows a path for a better, accurate, reliable and successful anti-cancer therapy in the future.