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

Autor:	Ho TC; Department of Biomedical Engineering, Columbia University, New York, NY, USA.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA., Kim HS; Department of Biomedical Engineering, Columbia University, New York, NY, USA.; Institute of Tissue Regeneration Engineering, Dankook University, Cheonan, Republic of Korea.; Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, Republic of Korea., Chen Y; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Li Y; Department of Biomedical Engineering, Tufts University, Boston, MA, USA., LaMere MW; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA., Chen C; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Wang H; Humanized Mouse Core Facility, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA., Gong J; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Palumbo CD; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.; Genomics Research Center, University of Rochester, Rochester, NY, USA., Ashton JM; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.; Genomics Research Center, University of Rochester, Rochester, NY, USA., Kim HW; Institute of Tissue Regeneration Engineering, Dankook University, Cheonan, Republic of Korea.; Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, Republic of Korea.; Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Republic of Korea.; Cell & Matter Institute, Dankook University, Cheonan, Republic of Korea., Xu Q; Department of Biomedical Engineering, Tufts University, Boston, MA, USA., Becker MW; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. michael_becker@urmc.rochester.edu kam.leong@columbia.edu., Leong KW; Department of Biomedical Engineering, Columbia University, New York, NY, USA. michael_becker@urmc.rochester.edu kam.leong@columbia.edu.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 May 19; Vol. 7 (21). Date of Electronic Publication: 2021 May 19 (Print Publication: 2021).
DOI:	10.1126/sciadv.abg3217
Abstrakt:	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) ribonucleoprotein [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 CXCL12α onto mesenchymal stem cell membrane-coated nanofibril (MSCM-NF) scaffolds mimicking the bone marrow microenvironment. In vitro, CXCL12α 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 CXCL12α-loaded LNP/MSCM-NF scaffolds provides an effective strategy for attenuating LSC growth to improve AML therapy. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze:	MEDLINE
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