Scaffold-mediated CRISPR-Cas9 delivery system for acute myeloid leukemia therapy

被引:68
|
作者
Ho, Tzu-Chieh [1 ,2 ]
Kim, Hye Sung [1 ,3 ,4 ]
Chen, Yumei [1 ]
Li, Yamin [5 ]
LaMere, Mark W. [2 ]
Chen, Caroline [1 ]
Wang, Hui [6 ]
Gong, Jing [1 ]
Palumbo, Cal D. [2 ,7 ]
Ashton, John M. [2 ,7 ]
Kim, HaeWon [3 ,4 ,8 ,9 ,10 ]
Xu, Qiaobing [5 ]
Becker, Michael W. [2 ]
Leong, Kam W. [1 ]
机构
[1] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA
[2] Univ Rochester, Med Ctr, Wilmot Canc Inst, Rochester, NY 14642 USA
[3] Dankook Univ, Inst Tissue Regenerat Engn, Cheonan, South Korea
[4] Dankook Univ, Coll Dent, Dept Regenerat Dent Med, Cheonan, South Korea
[5] Tufts Univ, Dept Biomed Engn, Boston, MA 02111 USA
[6] Columbia Univ, Columbia Ctr Translat Immunol, Humanized Mouse Core Facil, New York, NY USA
[7] Univ Rochester, Genom Res Ctr, Rochester, NY USA
[8] Dankook Univ, Dept Nanobiomed Sci, Cheonan, South Korea
[9] Dankook Univ, BK21 PLUS NBM Global Res Ctr Regenerat Med, Cheonan, South Korea
[10] Dankook Univ, Cell & Matter Inst, Cheonan, South Korea
关键词
AML STEM-CELLS; OSTEOGENIC DIFFERENTIATION; NANOPARTICLES; IL1RAP; NANOFIBRILS; EXPRESSION; EVOLUTION; BIOLOGY; PROTEIN; DNA;
D O I
10.1126/sciadv.abg3217
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Leukemia stem cells (LSCs) sustain the disease and contribute to relapse in acute myeloid leukemia (AML). Therapies that ablate LSCs may increase the chance of eliminating this cancer in patients. To this end, we used a bioreducible lipidoid-encapsulated Cas9/single guide RNA (sgRNA) ribonucleo-protein [lipidoid nanoparticle (LNP)-Cas9 RNP] to target the critical gene interleukin-1 receptor accessory protein (IL1RAP) in human LSCs. To enhance LSC targeting, we loaded LNP-Cas9 RNP and the chemokine CXCL12 alpha onto mesenchymal stem cell membrane-coated nanofibril (MSCM-NF) scaffolds mimicking the bone marrow microenvironment. In vitro, CXCL12 alpha release induced migration of LSCs to the scaffolds, and LNP-Cas9 RNP induced efficient gene editing. IL1RAP knockout reduced LSC colony-forming capacity and leukemic burden. Scaffold-based delivery increased the retention time of LNP-Cas9 in the bone marrow cavity. Overall, sustained local delivery of Cas9/IL1RAP sgRNA via CXCL12 alpha-loaded LNP/MSCM-NF scaffolds provides an effective strategy for attenuating LSC growth to improve AML therapy.
引用
收藏
页数:12
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