Engineered mesenchymal stem cell exosomes loaded with miR-34c-5p selectively promote eradication of acute myeloid leukemia stem cells

• Published in: Cancer letters 2023-10, Vol.575, p.216407-216407, Article 216407
• Main Authors: Wen, Jin, Chen, Ying, Liao, Chenxi, Ma, Xiao, Wang, Mengyuan, Li, Qian, Wang, Di, Li, Yingnan, Zhang, Xiaolan, Li, Lei, Zhou, Hao, Zou, Jing, Liu, Lingbo, Peng, Danyue
• Format: Article
• Language: English
• Subjects: CD123; CD44 fucosylation; Engineered exosomes; Leukemia stem cells; Mesenchymal stem cells
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2023.216407

Most patients with acute myeloid leukemia (AML) relapse eventually because of the inability to effectively eliminate leukemia stem cells (LSCs), prompting the search of new therapies to eradicate LSCs. Our previous study demonstrated that miR-34c-5p promotes the clearance of LSCs in an AML mouse model, highlighting its potential as a therapeutic target for eradicating LSCs, but the effective delivery of miR-34c-5p to LSCs remains a great challenge. Here, we employed simultaneous two-step modifications to engineer mesenchymal stem cells (MSCs) and MSC-derived exosomes to create exosomes overexpressing the fused protein lysosome-associated membrane protein 2-interleukin 3 (Lamp2b-IL3) and hematopoietic cell E-selectin/L-selectin ligand (HCELL), and demonstrated that the engineered exosomes exhibited an enhanced ability for bone marrow homing and selective targeting of LSCs. Additionally, using a humanized AML mouse model, we confirmed that the engineered exosomes, loaded with miR-34c-5p, could selectively promote eradication of LSCs and impede the AML development in vivo. In summary, we successfully designed an effective delivery system and provided new insights into the development of novel therapies for delivering miRNA or other molecules to LSCs with greater cellular targeting specificity. [Display omitted] •hUC-MSC derived exosomes overexpressing fusion protein Lamp2b-IL3 can enhance their targeting ability to LSCs.•FTVII-mediated α-1,3-exofucosylation on Lamp2b-IL3 exosomes converts CD44 to HCELL, enhancing their BM homing ability.•Engineered exosomes loaded with miR-34c-5p could selectively promote eradication of LSCs and impede the AML development.