Issue 9, 2021

Gene-editing by CRISPR–Cas9 in combination with anthracycline therapy via tumor microenvironment-switchable, EGFR-targeted, and nucleus-directed nanoparticles for head and neck cancer suppression

Abstract

Head and neck cancer (HNC) has a high incidence and a poor prognosis. Epirubicin, a topoisomerase inhibitor, is a potential anthracycline chemotherapeutic for HNC treatment. HuR (ELAVL1), an RNA-binding protein, plays a critical role in promoting tumor survival, invasion, and resistance. HuR knockout via CRISPR/Cas9 (HuR CRISPR) is a possible strategy for the simultaneous modulation of the various pathways of tumor progression. Multifunctional nanoparticles modified with pH-sensitive epidermal growth factor receptor (EGFR)-targeting and nucleus-directed peptides were designed for the efficient delivery of HuR CRISPR and epirubicin to human tongue squamous carcinoma SAS cells and SAS tumor-bearing mice. The pH-sensitive nanoparticles responded to the acidic pH value as a switch to expose the targeting peptides. The cellular uptake and transfection efficiency of these nanoparticles in SAS cells increased via EGFR targeting, ligand-mediated endocytosis, and endosomal escape. These nanoparticles showed low cytotoxicity towards normal oral keratinocyte NOK cells. CRISPR/Cas9 was transported into the nucleus via the nuclear directing peptide and successfully knocked out HuR to suppress proliferation, metastasis, and resistance in SAS cells. The multiple inhibition of EGFR/β-catenin/epithelial–mesenchymal transition pathways was mediated through modulating the EGFR/PI3K/mTOR/AKT axis. The co-treatment of epirubicin and HuR CRISPR in SAS cells further facilitated apoptosis/necroptosis/autophagy and caused cancer cell death. In combination with HuR CRISPR nanoparticles, the efficacy and safety of epirubicin nanoparticles against cancer in SAS tumor-bearing mice improved significantly. Collectively, these nanoparticles showed a tumor pH response, active EGFR targeting, and nuclear localization and thus offered a combinatorial spatiotemporal platform for chemotherapy and the CRISPR/Cas gene-editing system.

Graphical abstract: Gene-editing by CRISPR–Cas9 in combination with anthracycline therapy via tumor microenvironment-switchable, EGFR-targeted, and nucleus-directed nanoparticles for head and neck cancer suppression

Supplementary files

Article information

Article type
Communication
Submitted
06 may 2021
Accepted
09 iyl 2021
First published
29 iyl 2021

Nanoscale Horiz., 2021,6, 729-743

Gene-editing by CRISPR–Cas9 in combination with anthracycline therapy via tumor microenvironment-switchable, EGFR-targeted, and nucleus-directed nanoparticles for head and neck cancer suppression

C. Wang, C. Chang, T. Tzeng, A. M. Lin and Y. Lo, Nanoscale Horiz., 2021, 6, 729 DOI: 10.1039/D1NH00254F

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