A Duplex CRISPR-Cas9 Ribonucleoprotein Nanomedicine for Colorectal Cancer Gene Therapy.
Tao WanQi PanChongyi LiuJiajing GuoBowen LiXiaojie YanYiyun ChengYuan PingPublished in: Nano letters (2021)
Based on the high frequency of concurrent adenomatous polyposis coli (APC) and KRAS mutations and their strong cooperative interaction in human colorectal cancer (CRC) promotion, we herein develop a CRISPR-Cas9-based genome-editing nanomedicine to target both APC and KRAS mutations for the treatment of CRC. To this end, a hyaluronic acid (HA)-decorated phenylboronic dendrimer (HAPD) was designed for the targeted delivery of Cas9 ribonucleoprotein (RNP), by which both APC and KRAS genetic mutations harboring in CRC cells can be synergistically disrupted. Systemic administration of Cas9 RNP targeting APC and KRAS enabled by HAPD significantly inhibits tumor growth on xenografted and orthotopic CRC mouse models and also greatly prevents CRC-induced liver metastasis and lung metastasis. Thus, this duplex genome-editing system provides a promising gene therapy strategy for the treatment of human CRC and can be extended to other types of cancers with activated Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways.
Keyphrases
- genome editing
- crispr cas
- gene therapy
- high frequency
- wild type
- endothelial cells
- hyaluronic acid
- cell proliferation
- mouse model
- cancer therapy
- transcranial magnetic stimulation
- stem cells
- induced apoptosis
- induced pluripotent stem cells
- high glucose
- escherichia coli
- signaling pathway
- transcription factor
- squamous cell carcinoma
- cell cycle arrest
- pluripotent stem cells
- drug induced
- combination therapy
- locally advanced
- drug delivery
- genome wide
- epithelial mesenchymal transition
- cell death
- oxidative stress
- gold nanoparticles
- copy number
- smoking cessation